Antiviral azaindole derivatives

ABSTRACT

The invention comprises compounds of the class of azaindole piperazine diamide derivatives, compositions thereof and their use as anti-viral agents, and particularly for treating HIV infection.&lt;/PTEXT&gt;

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a Divisional application of application Ser. No. 09/912,710filed Jul. 25, 2001, now U.S. Pat. No. 6,476,034 which is acontinuation-in-part application of U.S. Non-Provisional applicationSer. No. 09/765,189 filed Jan. 18, 2001, now abandoned, which claims thebenefit of U.S. Provisional Application Ser. No. 60/184,004 filed Feb.22, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use. Inparticular, the invention is concerned with azaindole piperazine diamidederivatives that possess unique antiviral activity. More particularly,the present invention relates to compounds useful for the treatment ofHIV and AIDS.

2. Background Art

HIV-1 (human immunodeficiency virus −1) infection remains a majormedical problem, with an estimated 33.6 million people infectedworldwide. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 1999, 5.6 million newinfections were reported, and 2.6 million people died from AIDS.Currently available drugs for the treatment of HIV include sixnucleoside reverse transcriptase (RT) inhibitors (zidovudine,didanosine, stavudine, lamivudine, zalcitabine and abacavir), threenon-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdineand efavirenz), and five peptidomimetic protease inhibitors (saquinavir,indinavir, ritonavir, nelfinavir and amprenavir). Each of these drugscan only transiently restrain viral replication if used alone. However,when used in combination, these drugs have a profound effect on viremiaand disease progression. In fact, significant reductions in death ratesamong AIDS patients have been recently documented as a consequence ofthe widespread application of combination therapy. However, despitethese impressive results, 30 to 50% of patients ultimately failcombination drug therapies. Insufficient drug potency, non-compliance,restricted tissue penetration and drug-specific limitations withincertain cell types (e.g. most nucleoside analogs cannot bephosphorylated in resting cells) may account for the incompletesuppression of sensitive viruses. Furthermore, the high replication rateand rapid turnover of HIV-1 combined with the frequent incorporation ofmutations, leads to the appearance of drug-resistant variants andtreatment failures when sub-optimal drug concentrations are present(Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al;Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)).Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options.

Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections(Pedersen & Pedersen, Ref. 15). At least 30 different classes of NNRTIhave been described in the literature (De Clercq, Ref. 16) and severalNNRTIs have been evaluated in clinical trials. Dipyridodiazepinone(nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazinederivatives (delavirdine) have been approved for clinical use. However,the major drawback to the development and application of NNRTIs is thepropensity for rapid emergence of drug resistant strains, both in tissuecell culture and in treated individuals, particularly those subject tomonotherapy. As a consequence, there is considerable interest in theidentification of NNRTIs less prone to the development of resistance(Pedersen & Pedersen, Ref. 15).

Several indole derivatives including indole-3-sulfones, piperazinoindoles, pyrazino indoles, and 5H-indolo[3,2-b][1,5]benzothiazepinederivatives have been reported as HIV-1 reverse transciptase inhibitors(Greenlee et al, Ref. 1; Williams et al, Ref. 2; Romero et al, Ref. 3;Font et al, Ref. 17; Romero et al, Ref. 18; Young et al, Ref. 19; Geninet al, Ref. 20; Silvestri et al, Ref. 21). Indole 2-carboxamides havealso been described as inhibitors of cell adhesion and HIV infection(Boschelli et al, U.S. Pat. No. 5,424,329, Ref. 4). Finally,3-substituted indole natural products (Semicochliodinol A and B,didemethylasterriquinone and isocochliodinol) were disclosed asinhibitors of HIV-1 protease (Fredenhagen et al, Ref. 22).

Structurally related aza-indole amide derivatives have been disclosedpreviously (Kato et al, Ref. 23; Levacher et al, Ref. 24; Mantovanini etal, Ref. 5(a); Cassidy et al, Ref. 5(b); Scherlock et al, Ref. 5(c)).However, these structures differ from those claimed herein in that theyare aza-indole mono-amides rather than unsymmetrical aza-indolepiperazine diamide derivatives, and there is no mention of the use ofthese compounds for treating antiviral infections, particularly HIV.Nothing in these references can be construed to disclose or suggest thenovel compounds of this invention and their use to inhibit HIVinfection.

REFERENCES CITED Patent Documents

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4. Boschelli, D. H.; Connor, D. T.; Unangst, P. C. Indole-2-carboxamidesas inhibitors of cell adhesion. U.S. Pat. No. 5,424,329.

5. (a) Mantovanini, M.; Melillo, G.; Daffonchio, L. Tropyl7-azaindol-3-ylcarboxyamides as antitussive agents. PCT WO 95/04742(Dompe Spa). (b) Cassidy, F.; Hughes, I.; Rahman, S.; Hunter, D. J.Bisheteroaryl-carbonyl and carboxamide derivatives with 5HT 2C/2Bantagonists activity. PCT WO 96/11929. (c) Scherlock, M. H.; Tom, W. C.Substituted 1H-pyrrolopyridine-3-carboxamides. U.S. Pat. No. 5,023,265.

Other Publications

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SUMMARY OF THE INVENTION

The present invention comprises compounds of Formula I, orpharmaceutically acceptable salts thereof, which are effective antiviralagents, particularly as inhibitors of HIV.

wherein:

R₁, R₂, R₃, R₄ are each independently selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl,C₂-C₆ alkynyl, halogen, CN, phenyl, nitro, OC(O)R₁₅, C(O)R₁₅, C(O)OR₁₆,C(O)NR₁₇R₁₈, OR₁₉, SR₂₀and NR₂₁R₂₂;

R₁₅, is independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl and C₄-C₆ cycloalkenyl;

R₁₆, R₁₉, and R₂₀ are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₁₋₆ alkyl substituted with one to threehalogen atoms, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the oxygen or sulfur to which R₁₆, R₁₉, or R₂₀ isattached;

R₁₇ and R₁₈ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl and

C₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl or the carbon-carbontriple bond of said C₃-C₆ alkynyl are not the point of attachment to thenitrogen to which R₁₇ and R₁₈ is attached;

R₂₁ and R₂₂ are each independently selected from the group consisting ofH, OH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl,C₃-C₆ alkynyl and C(O)R₂₃; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₂₁ and R₂₂ is attached;

R₂₃ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl;

R₅ is (O)_(m), wherein m is 0 or 1;

n is 1 or 2;

R₆ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, C(O)R₂₄, C(O)OR₂₅, C(O)NR₂₆R₂₇, C₃-C₆alkenyl and C₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl or the carbon-carbontriple bond of said C₃-C₆ alkynyl are not the point of attachment to thenitrogen to which R₆ is attached;

R₂₄ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl;

R₂₅ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl;provided the carbon atoms which comprise the carbon-carbon triple bondof said C₃-C₆alkynyl are not the point of attachment to the oxygen towhich R₂₅ is attached;

R₂₆ and R₂₇ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, andC₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₂₆ and R₂₇ are attached;

R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selectedfrom the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl, CR₂₈R₂₉OR₃₀, C(O)R₃₁,CR₃₂(OR₃₃)OR34, CR₃₅NR36R₃₇, C(O)OR₃₈, C(O)NR₃₉R₄₀, CR₄₁R₄₂F, CR₄₃F₂ andCF₃;

R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₅, R₄₁, R₄₂ and R₄₃ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl and C(O)R₄₄;

R₃₃, R₃₄ and R₃₈ are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆cycloalkenyl, and C₃-C₆ alkynyl; provided the carbon atoms whichcomprise the carbon-carbon triple bond of said C₃-C₆ alkynyl are not thepoint of attachment to the oxygen to which R₃₄ and R₃₈ are attached;

R₃₆ and R₃₇ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₃₆ and R₃₇ are attached;

R₃₉ and R₄₀ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₃₉ and R₄₀ are attached;

R₄₄ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl;

Ar is selected from the group consisting of

A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄, C₁, C₂, C₃, D₁, D₂, and D₃ are eachindependently selected from the group consisting of H, CN, halogen, NO₂,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆alkynyl, OR₄₅, NR₄₆R₄₇, SR₄₈, N₃ and CH(—N═N—)—CF₃;

R₄₅ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl and C₃-C₆ alkynyl;provided the carbon atoms which comprise the carbon-carbon triple bondof said C₃-C₆ alkynyl are not the point of attachment to the oxygen towhich R₄₅ is attached;

R₄₆ and R₄₇ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl,C₃-C₆ alkynyl and C(O)R₅₀; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₅-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₄₆ and R₄₇ are attached;

R₄₈ is selected from the group consisting of H, C₁-C6 alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₃-C₆ alkynyl andC(O)R₄₉; provided the carbon atoms which comprise the carbon-carbontriple bond of said C₃-C₆ alkynyl are not the point of attachment to thesulfur to which R₄₈ is attached;

R₄₉ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and

R₅₀ is selected from the group consisting of H, C₁-C₆ alkyl, and C₃-C₆cycloalkyl.

Preferred are compounds of Formula I or pharmaceutically acceptablesalts thereof wherein R₂-R₄ is independently H, —OCH₃, —OCH₂CF₃, —OiPr,—OnPr, halogen, CN, NO₂, C₁-C₆ alkyl, NHOH, NH₂, Ph, SR₂₀, or N(CH₃)₂.

Also preferred are compounds of Formula I wherein one or two of R₇-R₁₄is independently methyl and the other substituents are hydrogen.

Also preferred are compounds of Formula I wherein one of A₁-A₅, B₁-B₄,C₁-C₃ or D₁-D₃ are either hydrogen, halogen, or amino and the remainingsubstituents are hydrogen.

Also preferred are compounds of the formula below:

wherein:

R₂ is H, F, Cl, Br, OMe, CN, or OH;

R₄ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl,Cl, OMe, CN, OH, C(O)NH₂, C(O)NHMe, C(O)NHEt, Ph or —C(O)CH₃;

n is 2;

R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are each independently H or CH3,provided up to two of these substituents may be methyl;

R₁ is hydrogen;

R₅ is unsubstituted; and

R₆ is hydrogen or methyl.

A most preferred aspect of the invention are compounds orpharmaceutically acceptable salts thereof of the Formula

wherein:

R₂ is H, —OCH₃, —OCH₂CF₃, —OPr, halogen, CN, NO₂, or NHOH;

R₄ is H, -halogen, —CN, or hydroxy;

One or two members of R₇-R₁₄ is methyl and the remaining members arehydrogen;

n is 2;

R₁ is hydrogen;

R₅ is (O)_(m), where m is O; and

R₆ is hydrogen, methyl, or allyl.

Another most preferred aspect of the invention are compounds of theformula below wherein:

wherein:

R₂ is selected from the group consisting of H, F, Cl, Br, OMe, CN, andOH;

R₄ is selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, Cl, OMe, CN, OH, C(O)NH₂,C(O)NHMe, C(O)NHEt, phenyl and —C(O)CH₃;

n is 2;

R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently H or CH₃,provided 0-2 of the members of the group R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, andR₁₄ may be CH₃ and the remaining members of the group R₈, R₉, R₁₀, R₁₁,R₁₂, R₁₃, and R₁₄ are H; and

R₆ is H or CH₃.

Another most preferred aspect of the inventions are compounds offormula:

wherein:

R₄ is selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, Cl, OMe, CN, OH, C(O)NH₂,C(O)NHMe, C(O)NHEt, phenyl and —C(O)CH₃;

n is 2;

R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently H or CH₃,provided 0-2 of the members of the group R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, andR₁₄ may be CH₃ and the remaining members of the group R₈, R₉, R₁₀, R₁₁,R₁₂, R₁₃, and R₁₄ are H; and

R₆ is H or CH₃.

Since the compounds of the present invention, may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present invention includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula I.

Another embodiment of the invention is a pharmaceutical compositionwhich comprises an antiviral effective amount of a compound of FormulaI.

Another embodiment of the present invention is a method for treatingmammals infected with a virus, wherein said virus is HIV, comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I.

Another embodiment of the present invention is a method for treatingmammals infected with a virus, such as HIV, comprising administering tosaid mammal an antiviral effective amount of a compound of Formula I incombination with an antiviral effective amount of an AIDS treatmentagent selected from the group consisting of: (a) an AIDS antiviralagent; (b) an anti-infective agent; (c) an immunomodulator; and (d) HIVentry inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The preparative procedures and anti-HIV-1 activity of the novelazaindole piperazine diamide analogs of Formula I are summarized below.The definition of various terms follow.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless thecontext indicates otherwise) means straight or branched chain alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, amyl, hexyl and the like. Similarly, “C₁₋₆ alkenyl” or “C₁₋₆alkynyl” includes straight or branched chain groups.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

Physiologically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this invention. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)- aminomethane), or with bases such as piperidine ormorpholine.

In the method of the present invention, the term “antiviral effectiveamount” means the total amount of each active component of the methodthat is sufficient to show a meaningful patient benefit, i.e., healingof acute conditions characterized by inhibition of the HIV infection.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially orsimultaneously. The terms “treat, treating, treatment” as used hereinand in the claims means preventing or ameliorating diseases associatedwith HIV infection.

The present invention is also directed to combinations of the compoundswith one or more agents useful in the treatment of AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of the AIDS antivirals, immunomodulators,antiinfectives, or vaccines, such as those in the following table.

Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse trans- criptase (RT)inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, (CGP-73547) Novartis AIDS, ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755)Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirusCurdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmuneCMV retinitis Immune globin Cytovene Syntex Sight threateningGanciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-UpjohnHIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddCHoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz DuPont Merck HIV infection, (DMP 266)AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl-inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one,STOCRINE EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FamciclovirSmith Kline herpes zoster, herpes simplex FTC Emory University HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion HIV infection, Roussel AIDS, ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC,AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersSquibb CMV infection Nelfinavir Agouron HIV infection, PharmaceuticalsAIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection,Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIVinhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide(Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIVPhosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine ValaciclovirGlaxo Wellcome Genital HSV & CMV infections Virazole Viratek/ICNasymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIVinfection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS BropiriminePharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC(Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labssarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma InterferonGenentech ARC, in combination w/TNF (tumor necrosis factor) GranulocyteGenetics Institute AIDS Macrophage Colony Sandoz Stimulating FactorGranulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex StimulatingFactor Granulocyte Schering-Plough AIDS, Macrophage Colony combinationStimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Granulocyte Amgen AIDS, in combination ColonyStimulating w/AZT Factor Remune Immune Response Immunotherapeutic Corp.rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS,ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combinationw/AZT SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of Nystatin Pastille oral candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM& IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal Meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Human Ortho Pharm. Corp. Severe anemia Erythropoietin assoc.with AZT Therapy Recombinant Human Serono AIDS-related Growth Hormonewasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment ofAnorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption Related to AIDS

Additionally, the compounds of the invention herein may be used incombinations which include more than three anti HIV drugs. Combinationsof four or even five HIV drugs are being investigated and the compoundsof this invention would be expected to be a useful component of suchcombinations.

Additionally, the compounds of the invention herein may be used incombination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5,May 2000, pp. 183-194.

It will be understood that the scope of combinations of the compounds ofthis invention with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable, but includes in principle any combination with any pharmaceuticalcomposition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments ofwith a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Finally a new proteaseinhibitor, BMS-232632, which is currently undergoing clinical trials maybecome a preferred inhibitor. Preferred non-nucleoside inhibitors of HIVreverse transcriptase include efavirenz. The preparation of ddC, ddl andAZT are also described in EPO 0,484,071. These combinations may haveunexpected effects on limiting the spread and degree of infection ofHIV. Preferred combinations include those with the following (1)indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddland/or ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC and/or3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TCand/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89;(5) zidovudine and lamivudine.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Parent azaindoles such as 4-azaindole, 5-azaindole, 6-azaindole, or7-azaindole are prepared by the methods described in the literature(Mahadevan et al, Ref. 25(a)) or Hands et. al. Ref 25 (b) are availablefrom commercial sources (7-azaindole from Aldrich Co.). This referenceand similar references show some examples of substituted aza indoles.Chemist skilled in the art can recognize that the general methodologycan be extended to azaindoles which have different substituents in thestarting materials. Azaindoles are also prepared via the routesdescribed in Scheme 1 and Scheme 2.

In Scheme 1, the Bartoli indole synthesis (Dobson et al, Ref. 25 (C)) isextended to prepare substituted azaindoles. Nitropyridine 22 was reactedwith an excess of vinyl magnesium bromide at −78° C. After warming up to−20° C., the reaction provides the desired azaindole 1. Generally thesetemperature ranges are optimal but in specific examples may be variedusually by no more than 20° C. but occasionally by more in order tooptimize the yield. The vinyl magnesium bromide may be obtainedcommercially as a solution in tetrahydrofuran or sometimes moreoptimally may be prepared fresh from vinyl bromide and magnesium usingliterature procedures which are well known in the art. Vinyl magnesiumchloride can also be used in some examples.

In Scheme 2, acetylene is coupled onto a halo-pyridine 23 using a Pd (0)catalyst to furnish 24. Subsequent treatment with base effectscyclization of 24 to afford azaindole 1 (Sakamoto et al, Ref. 26).Suitable bases for the second step include sodium methoxide or othersodium, lithium, or potassium alkoxide bases.

General procedures to prepare azaindole piperazine diamide 5 of FormulaI are described in Scheme 3 and Scheme 4.

An azaindole 1, was reacted with MeMgI (methyl magnesium iodide) andZnCl₂ (zinc chloride), followed by the addition of ClCOCOOMe (methylchlorooxoacetate) to afford aza-indole glyoxyl methyl ester 2 (Shadrinaet al, Ref. 27). Alternatively, compound 2 can be prepared by reactionof aza-indole 1 with an excess of ClCOCOOMe in the presence of AlCl₃(aluminum chloride) (Sycheva et al, Ref. 28). Hydrolysis of the methylester 2 affords a potassium salt 3 which is coupled withmono-benzoylated piperazine derivatives 4 in the presence of DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, to provideazaindole piperazine diamide 5 (Li et al, Ref. 29). The mono-benzoylatedpiperazine derivatives 4 can be prepared according to well establishedprocedures such as those described by Desai et al, Ref. 30(a), Adamczyket al, Ref. 30(b), Rossen et al, Ref. 30(c), and Wang et al, 30(d) and30(e).

An alternative method for the preparation of 5 involves treating anazaindole 1, obtained by procedures described in the literature or fromcommercial sources, with MeMgI and ZnCl₂, followed by the addition ofClCOCOCl (oxalyl chloride) in either THF (tetrahydrofuran) or ether toafford a mixture of desired products, glyoxyl chloride 6 and acylchloride 7, Scheme 4. The resulting mixture of glyoxyl chloride 6 andacyl chloride 7 is then coupled with mono-benzoylated piperazinederivatives 4 under basic conditions to afford product 5 as a mixture oftwo compounds (n =1 and 2).

General routes for further functionalizing azaindole rings are shown inSchemes 5. It should be recognized that the symbol Rx is meant torepresent a general depiction of the remaining substituents from R₄-R₂which are on the azaindole ring. As depicted in Scheme 5, the azaindolecan be oxidized to the corresponding N-oxide derivative 8 by using mCPBA(meta-Chloroperbenzoic Acid) in acetone or DMF (Dimethylformamide ) (eq.1, Harada et al, Ref. 31 and Antonini et al, Ref. 32). The N-oxide 8 canbe converted to a variety of substituted azaindole derivatives by usingwell documented reagents such as phosphorus oxychloride (POCl₃) (eq. 2,Schneller et al, Ref. 33(a)) or phosphorus tribromide (eq. 2, Wozniak etal, Ref. 33(b)), Grignard reagents RMgX (R=alkyl, X=Cl, Br or I) (eq. 4,Shiotani et al, Ref. 34), trimethylsilyl cyanide (TMSCN) (eq. 5,Minakata et al, Ref. 35), Ac₂O (eq. 6, Klemm et al, Ref. 36), thiol viaa sodium thiolate or other thiolates (eq. 7, Shiotani et al, Ref. 37),alcohol via metal alkoxides as in ref 37 or (eq. 8, Hayashida et al,Ref. 38), and amine (eq. 9, using ammonia or an amine in the presence ofTsCl in chloroform/water as in Miura et al, Ref. 39; or under similarconditions but with 10% aq NaOH also included as in Solekhova et al,Ref. 40). Under such conditions (respectively), a chlorine or bromineatom, nitrile group, alkyl group, hydroxyl group, thiol group, alkoxygroup and amino group can be introduced to the pyridine ring. Similarly,tetramethylamonnium fluoride (Me₄NF) transforms N-oxides 8 tofluoro-azaindoles (eq. 3). Further standard modification of OH groupwill provide alkoxy functionality as well (eq. 6).

Nitration of azaindole N-oxides results in introduction of a nitro groupto azaindole ring, as shown in Scheme 6 (eq. 10, Antonini et al, Ref.32). The nitro group can subsequently be displaced by a variety ofnucleophilic agents, such as OR, NR₁R² or SR, in a well establishedchemical fashion (eq. 11, Regnouf De Vains et al, Ref. 41(a), Miura etal, Ref. 41(b), Profft et al, Ref. 41(c)). The resulting N-oxides 16 arereadily reduced to the corresponding azaindole 17 using phosphorustrichloride (PCl₃) (eq. 12, Antonini et al, Ref. 32 and Nesi et al, Ref.42) or other reducing agents. Similarly, nitro-substituted N-oxide 15can be reduced to the azaindole 18 using phosphorus trichloride (eq.13). The nitro group of compound 18 can be reduced to either ahydroxylamine (NHOH) (eq.14, Walser et al, Ref. 43(a) and Barker et al,Ref. 43(b)) or an amino (NH₂) group (eq. 15, Nesi et al , Ref. 42 andAyyangar et al, Ref. 44) by carefully selecting different reducingconditions.

The alkylation of the nitrogen atom at position 1 of the azaindolederivatives can be achieved using NaH as the base, DMF as the solventand an alkyl halide or sulfonate as alkylating agent, according to aprocedure described in the literature (Mahadevan et al, Ref. 45) (eq.16, Scheme 7).

Halides can be converted to a variety of functionalities such as anitrile (eq. 17), an amino group (eq. 18), and or an alkoxy group (eq.19) 15 (Scheme 8) using well established procedures. Examples of thesetypes of transformations as depicted in eq. 17 are shown in Sakamoto etal (Ref. 46 (a) in which a copper cyanide is used to form a nitrile froma halide, Halley et al (Ref. 46 (b)) which provides nitriles via copperI cyanide in DMF, Yamaguchi et al (Ref. 46 (c)), Funhoff et al (Ref. 46(d)) uses CuCN in NMP, Shiotani et al (Ref. 37). Typically the reactionof CuCN to displace a halide requires heating. Temperatures such as 145°C. for 18 h have been found to be preferred but these conditions may bevaried. The temperature may be raised or lowered by up to 100° C. andreaction times may vary from as little 30 minutes to as long as 80 hdepending on reaction temperature and substrate. As an alternative toEq. 17, Klimesova et al uses a primary amide precursor (which can comefrom the carboxylic acid as described elsewhere) and phosphorus oxychloride to generate a nitrile (Ref. 47) and Katritzky et al (Ref.48).As shown in eq 18 halides can be displaced with amines or ammonia. Someexample conditions are contained in Shiotani et. al. reference 37 and inKatritzky et.al. reference 48. For example heating the halide 9 in anexcess of a primary or secondary amine as solvent at a temperature ofreflux (or between 20° C. and 200° C.) will result in displacement ofthe halide to provide amines 27. In the instance of ammonia or volatileamines, a pressure reactor as described in in Katritzky et.al. reference48 can be utilized to carry out the reaction without losing the volatileamine during heating. The reactions may be monitored by TLC or or liquidchromatography and the reaction temperature increased until reaction isobserved. Cosolvents such as dioxane or pyridine may be utilized whenthe amine is costly. An alternative method would employ the modifiedpalidium catalysis methods of Hartwig (Yale) or Buchwald (MIT) to effectdisplacement under milder conditions. As shown in eq. 19 of Scheme 8,alkoxides may be used to displace halogens in 9 and provide ethers 26.Typically this transformation is best carried out by adding sodium to asolution of the parent alcohol to generate an alkanoate. Alternatively astrong base such as NaH, or NaN(SiMe₃)₂ may be employed. Thecorresponding lithium or potassium bases or metals may also be utilized.Usually, an excess of base with respect to the halide to be displaced isemployed. Between two and twenty equivalents of alkanoate are usuallyused with ten being preferred. The reaction is carried out at reflux ora temperature of between 30° C. and 200° C. Typically approximately 80°C. is useful. The reaction may take from four to eighty hours to reachcompletion with times between 12 and 48 hours being typical. Asdescribed above for eq. 18, the reaction progress may be monitored.Typical conditions for displacement with sodium methoxide in methanolare provided in Shiotani et.al. reference 37 in the general procedureused for the preparation of examples 5a, 5c, and 6 of the reference.

The nitrile group can be converted to a carboxylic acid 28 (eq. 20,using aqueous sodium hydroxide in ethanol as in Miletin et al, Ref. 49(a); or using KOH in aqueous ethanol as in Shiotani et al, Ref. 49 (b);or using 6N HCl as in El Hadri et al, Ref 49 (c)). The nitrile group canbe converted to an ester 29 (eq. 21, using sodium methoxide in methanolas in Heirtzler et al, Ref. 50 (a); or using HCl in methanol as inNorrby et al, Ref. 50 (b)). The nitrile group can be converted to anamide 30 (eq. 22, using sulfuric acid as in Sitsun'Van et al, Ref. 51(a); or using acetic acid, tertbutanol, sulfuric acid, and acetonitrileas in Reich et al, 51 (b); or using MeOS(O)₂F as in Salfetnikova et al,51 (c)).

In Scheme 10, the methyl group on the pyridine ring can be also oxidizedto a carboxylic acid 28 using K₂Cr₂O₇ in 98% sulfuric acid as in (eq.23, Oki et al, Ref. 52 (a); or using Chromium trioxide in conc sulfuricacid as in Garelli et al, Ref. 52 (b); or using selenium dioxide inpyridine as in Koyama et al, Ref. 52 (c)). The carboxylic acid may betransformed to an ester 29 using HCl in 10% methanol as in (eq. 24,Yasuda et al, Ref. 53 (a); or using thionyl chloride followed by asodium alkyl alkoxide as in Levine et al, 53 (b); or using an alcoholand PyBOP in NMM, DMAP, and DMF as in Hoemann, 53 (c)). )). Thecarboxylic acid may be transformed to an amide 30 using aqueous KOHfollowed by oxalyl chloride in benzene followed by triethylamine indichloromethane as in (eq. 25, Norman et al, Ref. 54 (a); or by heatingan amine with the acid as in Jursic et al, 54 (b); or by coupling anamine to the acid with N,N-carbonyldiimidazole Strekowski et al, 54 (c);or by using oxalyl chloride in diethylether and an amine as in Shi etal, 54 (d)).

An alternative strategy for the synthesis of compounds containing variedsubstituents Ar is shown in Scheme 11. The benzamide moiety of thediamide 5 can be selectively hydrolyzed using to give intermediate 31.Coupling of amine 31 with with other carboxylic acids under DEBPT andbase using conditions described above for earlier couplings, providesother novel diamides 5.

The preparation of compound 35 shown in Scheme 12 was carried out fromcommercially available 32 as described in Clark, G. J., Reference 56.The Bartoli methodology described in Scheme 1 was used to prepare4-methoxy-6-azaindole 36. Reduction of the bromides using transferhydrogenation provided the desired 4-methoxy indole 37. Compound 36could be converted into a separable mixture of monobromides viaselective lithium bromine exchange using t-Buli at cold temperatures ofbetween −100 to −78° followed by a quench with ammonium chloride. Thealternate methodology described in Scheme 3 for acylation with chloromethyl oxalate at the 3-position was applied to 37 as shown and providedintermediate 38. The methodology of Scheme 3 could then be followed toprovide compound 39. While the methodology in Scheme 12 is the preferredroute for preparing compound 39 and other compounds of formula I, analternative route which is depicted in Scheme 13 was developed forpreparing such compounds. Pyrrole 40 was prepared via the methoddescribed in Anderson, H. J., reference 57; Hydrolysis of ester 40 usingstandard conditions such as potassium hydroxide in ethanol at ambienttemperature for ˜2 h or until completion provided potassium2-pyrrolecarboxaldehyde4-oxoacetate. A solution of this carboxylatesalt, N-benzoylpiperazine hydrochloride,3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin4(3H)-one and triethylaminein DMF was stirred for approximately one day or until completion toprovide after workup and crystallization amide 41. Amide/aldehyde 41 wasstirred as a slurry in EtOH for a short time of from 1 to 60 min.,cooled to 0 ° C. (or between −15 and 20°) and then was stirred withglycine methyl ester hydrochloride, triethylamine (or alternativelyHunig's base, 2,6-Lutidine, or no base), and sodium cyanoborohydride toprovide amine 42. This transformation could also be carried out usingaldehyde 41, glycine methyl ester hydrochloride, and sodium triacetoxyborohydride in either dichloromethane, tetrahydrofuran, or C₁-C₄ alcoholsolvents. Alternatively, the free base of glycine methyl ester could besubstituted in either procedure and a dehydrating agent such asmolecular sieves could be employed in the reaction prior to addition ofthe borohydride reducing agent. Alternatively this transformation couldbe carried out by first protecting the pyrrole nitrogen with a benzoyl(from benzoyl chloride and tertiary amine) or benzyl moiety (benzylbromide, NaH or DBU in THF). The protecting groups can be removed whendesired using hydrolysis with aqueous base or hydrogenationrespectively. The methyl ester 42 was hydrolyzed using potassiumcarbonate in methanol to provide after acidification with HCl thecorresponding carboxylic acid. The acid was placed in anhydrousmethanesulfonic acid containing phosphorus pentoxide which had beenpreheated for between 15 and 40 minutes and heated at approximately 110°(usually between 90 and 150°) for a short time of approximately 15minutes but usually less than an hour and then poured over ice.Acylation or benzoylation of the product using for example modifiedSchotten-Bauman conditions (dichloromethane, potassium carbonate, andbenzoyl chloride) provided ketone 43. Reaction with dimethoxy propaneand anhydrous p-toluenesulfonic acid generates an intermediate enolether which upon reaction with chloranil provided compound 39. The enolether can alteratively be prepared using trimethyl ortho acetate and asulfonic acid catalyst. Azaindoles such as 39 can be functionalized intonitrites which are versatile intermediates by oxidation to the N-oxidefollowed by reaction with DEPC and TEA or phosphorus oxychloridefollowed by CuCN in DMF. Details for reactions which convert 41 into43-45 using these conditions on a similar substrate are described inreference 58 which is Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.;Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami, Y., Tetrahedron,1997, 53(5), 1593-1606. It should be apparent that in Schemes 12 and 13,4b may be replaced with any of the substrates represented by formula 4in Scheme 4. It should also be apparent that indole 37, 39, 44, and 45may be elaborated using appropriate chemistry described in the Schemes5-11 herein which describe general methodology for functionalization ofthe azaindoles.

It should be noted that 2-chloro-5-fluoro-3-nitro pyridine may beprepared by the method in example 5B of reference 59 Marfat et.al. Thechemistry in Schemes 1 and 3 to provide the derivative which correspondsto general formula 5 and has a 6-aza ring and R₂=F and R₄=Cl. Inparticular, reaction of 2-chloro-5-fluoro-3-nitro pyridine with 3equivalents of vinyl Magnesium bromide using the typical conditionsdescribed herein will provide 4-fluoro-7-chloro-6-azaindole in highyield. Addition of this compound to a solution of aluminum trichloridein dichlorometane stirring at ambident temperature followed 30 minuteslater with chloromethyl or chloroethyl oxalate provides an ester.Hydrolysis with KOH as in the standard procedures herein provides anacid salt which reacts with piperazines 4 (for example 1-benzoylpiperazine) in the presence of DEPBT under the standard conditionsdescribed herein to provide the compound described just above. Thecompound with the benzoyl piperazine isN-(benzoyl)-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazineand is compound 5av. The 7-chloro moiety in 5av can be utilized by themethods of this invention to provide the desired derivatives where R₄ issubstituted according to the general claim. For example, exposure of 5avto sodium methoxide in refluxing methanol will provide the compound 5ayin which the 6-azaindole ring contains a 4-fluoro-and 7-methoxysubstituent. Alternatively, the 4-fluoro-7-chloro-6-azaindole may bereacted with sodium methoxide and then carried through the sequence asabove to provideN-(benzoyl)-N′-[(4-fluoro-7-methoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine,5ay. 4-fluoro-7-chloro-6-azaindole can also be reacted with CuCN/DMF asdescribed in eq. 17 to provide a 7-cyano intermediate which can behydrolyzed to an acid as described in eq. 21 Scheme 9 using HCI in MeOHat RT for 12h followed by reflux to complete the reaction. The acid canbe smoothly converted to to a methly ester by adding diazomethane inether to a stitting solution of the acid in diazometane at ambienttemperature or lower. These are the standard conditions for usingdiazomethane which is conveniently generated as a solution in diethylether from Diazald® based on instructions which come with a kit fromAldrich Chemical Co. The methyl ester may be carried through theacylation using oxalyl chloride as shown in Scheme 4, followed bycoupling with a piperazine (benzoyl piperazine for example) to generatethe corresponding 4-fluoro-7-carbomethoxy-6-azaindole which uponaddition to a solution of methylamine in water would provide 5az whichisN-(benzoyl)-N′-[(4-fluoro-7-(N-methyl-carboxamido)-6-azaindol-3-yl)-oxoacetyl]-piperazine.The same sequences of chemistry described above for4-fluoro-7-chloroindole may be carried out using 7-chloro-4aza-indoleand (R)-3-methyl-N-benzoylpiperazine 4a to provide 5abc which is(R)-N-(benzoyl)-3-methyl-N′-[(7-methoxy-4-azaindol-3-yl)-oxoacetyl]-piperazineor 5abd which is(R)-N-(benzoyl)-3-methyl-N′-[(7-(N-methyl-carboxamido)-4-azaindol-3-yl)-oxoacetyl]-piperazine.The starting 7-chloro4-aza-indole is compound 11 and its prepartion isdescribed as in example in the experimental section.

It should be clear that in addition to compounds 5a-5abd compounds 8,11-30, 39, 44, and 45 are all compounds of formula I and are within thescope of the invention.

Detailed descriptions of many of the preparations of piperazine analogsof compounds of this invention and conditions for carrying out thegeneral reactions described herein are described in PCT WO 00/76521published Dec. 21, 2000.

In the general routes for substituting the azaindole ring describedabove, each process can be applied repeatedly and combinations of theseprocesses are permissible in order to provide azaindoles incorporatingmultiple substituents. The application of such processes providesadditional compounds of Formula I.

Antiviral Activity

The antiviral activity of compounds was determined in HeLa CD4 CCR5cells infected by single-round infectious HIV-1 reporter virus in thepresence of compound at concentrations≦10 μM. The virus infection wasquantified 3 days after infection by measuring luciferase expressionfrom integrated viral DNA in the infected cells (Chen et al, Ref. 55).The percent inhibition for each compound was calculated by quantifyingthe level of luciferase expression in cells infected in the presence ofeach compound as a percentage of that observed for cells infected in theabsence of compound and subtracting such a determined value from 100.Compounds exhibiting anti-viral activity without appreciable toxicity atconcentrations≦10 μM are presented in Table I.

TABLE I

Average % inhibition Compd # n R₇₋₁₄ at or < 10 μM 5a 2 R₇₋₁₃ = H, R₁₄ =(R)-Me >99%   5b 2 R₇₋₈ = R₁₀₋₁₄ = H, R₉ = Et 90% 5c 1 R₇₋₈ = R₁₀₋₁₄ =H, R₉ = Et 80% 5d 2 R₇₋₁₄ = H 98% 5e 2 R₇₋₈ = R₁₀₋₁₄ = H, R₉ = Me 80% 5f2 R₇₋₁₃ = H, R₁₄ = (S)-Me 80% 5g 2 R₇₋₁₃ = H, R₁₄ = Et 70% 5h 2 R₇₋₁₂ =H, R₁₃ = R₁₄ = Me 80% 5i 2 R₇₋₈ = R₁₀₋₁₃ = H, R₉ = R₁₄ = Me 89%

Average % inhibition at Compound # R R₁₄ or < 10 μM 5j H H 90% 5k H(R)-Me >99%  

Average % inhibition at Compound # R R₁₄ or < 10 μM 5l H (R)-Me >99%  

Average % inhibition at Compound # R R₁₄ or < 10 μM 5n H (R)-Me 93%

Ave. % inhibition at Compound # or < 10 μM 5m 60%

Average % inhibition at Compound # R₂ or < 10 μM  8a H 90% 15a NO₂ 70%16a OMe >99%   16d OEt 88% 16e SPr 50%

Average % inhibi- Comp tion at or # R₂ R₄ R₁₄ < 10 μM  9a Cl H(R)-Me >99%    9b H Cl (R)-Me >99%   10a NO₂ F (H)-Me >99%   11a H (whenR₄ = Me), Me (when R₂ = H), (R)-Me 99% Me (when R₄ = H) H (when R₂ = Me)11b H (when R₄ = Ph), Ph (when R₂ = H), (R)-Me 85% Ph (when R₄ = H) H(when R₂ = Ph) 11c H (when Vinyl (when (R)-Me 48% R₄ = vinyl), Vinyl R₂= H), H (when (when R₄ = H) R₂ = Vinyl) 12a H CN (R)-Me >99%   14a H OH(R)-Me >99%   17a OMe H (R)-Me >99%   17d OMe H (S)-Me 98% 17e OMe H Me94% 17b OCH₂CF₃ H (R)-Me 99% 17c O-i-Pr H (R)-Me >99%   18a NO₂ H (R)-Me80% 19a NHOH H (R)-Me 98% 20a NH₂ H (R)-Me 95% 17f H PrS (R)-Me >99%  

Compound # Average % inhibition at or < 10 μM 13a >99%

Average % inhibition at Compound # R or < 10 μM 21a Me 70% 21b—CH2—CH═CH2 95%

Compound Average % inhibition at # R R₁₄ or < 10 μM 5p H H 40% 5r H(R)-Me >99%   5s H (S)-Me 56% 5q H Me 97% 5t Cl H >99%   5u Cl (R)-Me99% 5v OMe (R)-Me >99%   27c NMe₂ (R)-Me 63%

Compound # Average % inhibition at or < 10 μm 8b 91%

Average % inhibition Compound # R₄ R at or < 10 μm 5w H H 98% 5x Me H99% 5y Cl H >99%   5z OMe Me 97%

EXPERIMENTAL PROCEDURES Biology

In Table I and hereafter, the following definitions apply.

“μM” means micromolar;

“ml” or “mL” means milliliter;

“μl” means microliter;

“mg” means milligram;

“nM” means nanomolar

“a” refers to percent inhibition data as representing the mean values ofat least two experiments with duplicate determinations in eachexperiment.

The materials and experimental procedures used to obtain the resultsreported in Table I are described below.

Cells

Virus production—Human embryonic Kidney cell line, 293, propagated inDulbecco's Modified Eagle Medium (Life Technologies, Gaithersburg, Md.)containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.).

Virus infection—Human epithelial cell line, HeLa, expressing the HIV-1receptors CD4 and CCR5 was propagated in Dulbecco's Modified EagleMedium (Life Technologies, Gaithersburg, Md.) containing 10% fetalBovine serum (FBS, Sigma, St. Louis, Mo.) and supplemented with 0.2mg/ml Geneticin (Life Technologies, Gaithersburg, Md.) and 0.4 mg/mlZeocin (Invitrogen, Carlsbad, Calif.).

Virus—Single-round infectious reporter virus was produced byco-transfecting human embryonic Kidney 293 cells with an HIV-1 envelopeDNA expression vector and a proviral cDNA containing an envelopedeletion mutation and the luciferase reporter gene inserted in place ofHIV-1 nef sequences (Chen et al, Ref. 55). Transfections were performedusing lipofectAMINE PLUS reagent as described by the manufacturer (LifeTechnologies, Gaithersburg, Md.).

Experiment

1. Compound was added to HeLa CD4 CCR5 cells plated in 96 well plates ata cell density of 5×10⁴ cells per well in 100 μl Dulbecco's ModifiedEagle Medium containing 10% fetal Bovine serum at a concentration of <20μM.

2. 100 μl of single-round infectious reporter virus in Dulbecco'sModified Eagle Medium was then added to the plated cells and compound atan approximate multiplicity of infection (MOI) of 0.01, resulting in afinal volume of 200 μl per well and a final compound concentration of<10 μM.

3. Samples were harvested 72 hours after infection.

4. Viral infection was monitored by measuring luciferase expression fromviral DNA in the infected cells using a luciferase reporter gene assaykit (Roche Molecular Biochemicals, Indianapolis, Ind.). Infected cellsupernatants were removed and 50 μl of Dulbecco's Modified Eagle Medium(without phenol red) and 50 μl of

Method for Extrapolating % Inhibition at 10μM

The data in Table 1 was obtained using the general procedures above andby the following methods. Data is not reported for all compounds sincedata for all the compounds is reported by the alternate method in Table2. The percent inhibition for each compound was calculated byquantifying the level of luciferase expression in cells infected in thepresence of compound as a percentage of that observed for cells infectedin the absence of compound and subtracting such a determined value from100. For compounds tested at concentrations less than 10 μM, the percentinhibition at 10 μM was determined by extrapolation using the XLfitcurve fitting feature of the Microsoft Excel spreadsheet software.Curves were obtained from 10 data points (% inhibition determined at 10concentrations of compound) by using a four parameter logistic model(XLfit model 205: y=A+((B−A)/(1+((C/x)^(D)))), where, A=minimum y,B=maximum y, C=logEC₅₀, D=slope factor, and x and y are known datavalues. Extrapolations were performed with the A and B parametersunlocked.

Biological Data Expressed as an EC₅₀

Table 2 presents the data for the compounds grouped based on their EC₅₀which provides an additional method for comparing the antiviral potencyof the compounds of this invention. These values were calculated by thefollowing method. The effective concentration for fifty percentinhibition (EC50) was calculated with the Microsoft Excel XLfit curvefitting software. For each compound, curves were generated from percentinhibition calculated at 10 different concentrations by using a fourparamenter logistic model (model 205).

TABLE 2 Biological Data Expressed as EC₅₀s Compounds Compounds* withEC₅₀s > 1 Compounds with with EC₅₀s μM but <5 μM EC₅₀ < 1 μM >0.4 μM:5ac. 5h, 11b, 18a, 5a, 5b, 5c, 5d, 5e, >0.5 μM: 5m, 5p, 5f, 5g, 5i, 5j,5k, 5l, 5s, 5ab, 5ad, 5n, 5q, 5r, 5t, 5u, 5ae, 16b, 16c, 5v, 5w, 5x, 5y,5z, 16h, 17f, 17g, 5ai, 5ak, 5an, 17h. 5ao, 5ap, 8a, 8b, >5 μM: 5af,5ag, 9a, 9b, 10a, 5ah, 8e, 11c, 11a, 12a, 13a, 15a, 16e, 17g, 16a, 16d,17a, 17b, 17c, 17d, 17e, 19a, 20a, 21a, 21b, 27c, 39 *Some of thesecompounds were tested at a concentration lower than their EC₅₀ butshowed some ability to cause inhibition and thus should be evaluated ata higher concentration to determine the exact EC₅₀. An approximateattempt to exclude compounds which did not show some potential forinhibition (those which might have an EC50 > 100 uM) was made.

Chemistry

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

LC/MS Method (i.e., Compound Identification)

Column A: YMC ODS-A S7 3.0×50 mm column

Column B: PHX-LUNA C18 4.6×30 mm Column

Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B

Gradient time: 2 minutes

Hold time 1 minute

Flow rate: 5 ml/min

Detector Wavelength: 220 nm

Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid

Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid

Compounds purified by preparative HPLC were diluted in methanol (1.2 ml)and purified using the following methods on a Shimadzu LC-10A automatedpreparative HPLC system.

Preparative HPLC Method (i.e., Compound Purification)

Purification Method: Initial gradient (30% B, 70% A) ramp to finalgradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0%A)

Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid

Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid

Column: YMC C18 S5 20×100 mm column

Detector Wavelength: 220 nm

Typical Procedures and Characterization of Selected Examples TypicalProcedure for the Preparation of Compounds in Scheme 1 1) Preparation ofAzaindole 1

Preparation of azaindole, Method A: Preparation of 7-Chloro-6-azaindole1e: 2-Chloro-3-nitropyridine 22e (5.0 g) was dissolved in dry THF (200ml). After the solution was cooled down to −78° C., an excess of vinylmagnesium bromide (1.0 M in THF, 100 ml) was added. Then, the reactionwas left at −20° C. for eight hours before quenched with 20% NH₄Cl (150ml). The aqueous phase was extracted with EtOAc (3×150 ml). The combinedorganic layer was dried over MgSO₄. After filtration and concentration,the crude product was purified by silica gel column chromatography toafford 1.5 g of 7-chloro-6-azaindole 1e in 31% yield.

Summarized below is the characterization of compounds 1 with thefollowing structures:

Compound 1e, R=Cl, 7-Chloro-6-azaindole: ¹H NMR (500 MHz, CD₃OD) δ 7.84(d, 1H, J=7.95 Hz), 7.76 (m, 2H), 6.61 (d, 1H, J=5.45 Hz). MS m/z:(M+H)⁺ calcd for C₇H₆ClN₂: 153.02; found 152.93. HPLC retention time:0.51 minutes (column A).

Compound 1f, R=OMe, 7-Methoxy-6-azaindole: MS m/z: (M+H)⁺ calcd forC₈H₉N₂O: 149.07; found 149.00. HPLC retention time: 0.42 minutes (columnA).

Characterization of compounds 1 with the following substructure preparedby the method above:

Compound 1g, R₂=H, R₄=Me, 7-Methyl4-azaindole: MS m/z: (M+H)⁺ calcd forC₈H₉N₂: 133.08; found 133.01. HPLC retention time: 0.34 minutes (columnA).

Compound 1ak, R₂=Cl, R₄=Me, 5-Chloro-7-methyl4-azaindole: MS m/z: (M+H)⁺calcd for C₈H₈ClN₂: 167.04; found 166.99. HPLC retention time: 1.22minutes (column B).

Preparation of azaindole, Method A: Preparation of7-Benzyloxy-4-azaindole 1j: To a solution of benzyl alcohol (16.6 g) in200 ml of DMF was added NaH (4.8 g) slowly. The mixture was stirring atroom temperature for 2 hours to afford sodium benzoxide, which wastransferred into a solution of 4-chloro-3-nitropyridine hydrochloride22j (20 g) in DMF (100 ml). The resulting mixture was kept stirring for10 hours before quenched with water. After DMF was removed under vaccum,the crude product was suspended in water and extracted with EtOAc (3×250ml). The organic phase was dried over MgSO₄ and concentrated to give aresidue, which was purified via recrystallization to afford 6.1 g of4-benzoxy-3-nitropyridine 22j.

Characterization of Compound 22j:

4-benzyloxy-3-nitropyridine: MS m/z: (M+H)⁺ calcd for C₁₂H₁₁N₂O₃:231.08; found 231.06. HPLC retention time: 1.46 minutes (column A).

Preparation of compound 1j, 7-benzoxy-4-azaindole: The general procedureand conditions described for the Bartoli-type reaction used to prepare1e were followed.

Characterization of Compound 1j:

Compound 1j, 7-benzyloxy-4-azaindole: ¹H NMR (500 MHz, CDCl₃) δ 8.64 (b,1H), 8.34 (d, 1H, J=5.35 Hz), 7.40 (m, 6H), 6.72 (d, 1H, J=3.25 Hz),6.67 (d, 1H, J=5.45 Hz), 5.35 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 151.1,147.9, 145.2, 135.8, 128.8, 128.6, 127.9, 126.3, 119.6, 103.9, 99.6,70.2. MS m/z: (M+H)⁺ calcd for C₁₄H₁₃N₂O: 225.10; found 225.03. HPLCretention time: 1.11 minutes (column A).

Preparation of Azaindole, Typical Example for Method B: Preparation of7-Chloro4-azaindole 1i:

An excess of SnCl₂ (25 g) was cautiously added into a solution of4-chloro-3-nitropyridine hydrochloride (5 g) in concentrated HCl and thereaction was stirred for 12 hours. Concentration under pressure provideda mixture, which was neutralized with 2N NaOH to pH 6-7. The aqueousphase was extracted with EtOAc (5×100 ml). The organic layers were thencombined, dried over anhydrous MgSO₄ and concentrated in vacuo to give acrude product (2.2 g), which was 4-chloro-3-nitropyridine which was pureenough for direct use in further reactions.

7g of the crude product from the previous step was dissolved in 200 mlof TFA. Then, 10.7 g of NBS was added into the mixed solutioncautiously. After 8 hours, solvent was removed under vacuum. The residuewas dissolved in 2N NaOH (200 ml) and aqueous layer was extracted withEtOAc (3×200 ml). The combined organic layer was dried over MgSO₄ andconcentrated to provide a crude product with was purified viarecrystallization in hexane to afford 5 g of3-amino-2-bromo-4-chloropyridine.

Characterization of 3-Amino-2-bromo4-chloropyridine:

MS m/z: (M+H)⁺ calcd for C₅H₅BrClN₂: 206.93; found 206.86. HPLCretention time: 1.32 minutes (column B).

To a solution of 3-amino-2-bromo4-chloropyridine in 250 ml of ether wasadded 8.4 g of trifluoroacetic anhydride at 0° C. 5.3 g of Na₂CO₃ wasadded 10 minutes later, and the reaction mixture was stirred at roomtemperature for 10 hours before the reaction was quenched with water(100 ml). The aqueous phase was extracted with EtOAc (3×150 ml). Thecombined organic layer was dried over MgSO₄ and concentrated to give aresidue, which was purified by silica gel column chromatography toafford 3.7 g of compound 23i.

Characterization of Compound 23i:

2-Bromo-4-chloro-3-trifluoroacetaminopyridine: MS m/z: (M+H)⁺ calcd forC₇H₄BrClF₃N₂O: 302.90; found 302.91. HPLC retention time: 1.48 minutes(column B).

A mixture of compound 23i (0.9 g), trimethylsilylacetylene (0.49 g),PdCl₂(PPh₃)₂ (0.1 g) and CuI (0.05 g ) in Et₃N (1.5 ml) was heated to100° C. in sealed tube for 10 hours. Then, solvent was removed undervaccum. The residue was partitioned between water (10 ml) and EtOAc (10ml). Aqueous phase was extracted with EtOAc (2×10 ml). The combinedorganic layer was dried over MaSO₄ and concentrated under vaccum toprovide a crude product 24i which was used in the further reactionwithout purification.

Characterization of Compound 24i:

Compound 24i,4-Chloro-3-trifluoroacetamido-2-(trimethylsilylethynyl)pyridine: MS m/z:(M+H)⁺ calcd for C₇H₄BrClF₃N₂O: 321.04; found 320.99. HPLC retentiontime: 1.79 minutes (column B).

A mixture of compound 24i (0.28 g) and sodium ethoxide (0.30 ml) in 20ml of ethanol was heated to reflux for 10 hours under nitrogenatmosphere. After solvent removed under vaccum, the residue was purifiedusing Shimadzu automated preparative HPLC System to give compound 1i(0.1 g).

Characterization of Compound 1i:

Compound of 1i 7-Chloro-4-azaindole: ¹H NMR (500 MHz, CD₃OD) δ 8.50 (d,1H, J=6.20 Hz), 8.10 (d, 1H, J=3.20 Hz), 7.71 (d, 1H, J=6.30 Hz), 6.91(d, 1H, J=3.25 Hz). MS m/z: (M+H)⁺ calcd for C₇H₆ClN₂: 153.02; found152.90. HPLC retention time: 0.45 minutes (column A).

1) Preparation of Azaindole 3-Glyoxylmethyl Ester 2

Acylation of azaindole, method A: Preparation of Methyl(7-azaindol-3-yl)-oxoacetate 2a: To a solution of 7-azaindole 1a (20.0g, 0.169 mol) in dry CH₂Cl₂ (1000 ml), 62.1 ml of MeMgI (3.0M in Et₂O,0.186 mol) was added at room temperature. The resulting mixture wasstirred at room temperature for 1 hour before ZnCl₂ (27.7 g, 0.203 mol)was added. One hour later, methyl chlorooxoacetate (24.9 g, 0.203 mol)was injected into the solution dropwise. Then the reaction was stirredfor 8 hours before being quenched with methanol.

After all solvents were evaporated, the residue was partitioned betweenethyl acetate (500 ml) and H₂O (300 ml). The aqueous phase wasneutralized with saturated Na₂CO₃ to pH 6-6.5, and extracted with EtOAc(3×500 ml). The organic layers were then combined, washed with 0.1N HCl(3×200 ml), dried over anhydrous MgSO₄ and concentrated in vacuo to givea crude product 2a (14.3 g, 41.5%), which was pure enough for thefurther reactions.

Acylation of azaindole, method B: Preparation of Methyl(5-azaindol-3-yl)-oxoacetate 2b: 5-Azaindole 1b (0.5 g, 4.2 mmol) wasadded to a suspension of AlCl₃ (2.8 g, 21.0 mmol) in CH₂Cl₂ (100 ml).Stirring was continued at room temperature for 1 hour before methylchlorooxoacetate (2.5 g, 21.0 mmol) was added dropwise. The reaction wasstirred for 8 hours. After 20 ml of MeOH was added cautiously to quenchthe reaction, solvents were removed under vaccum. The solid residue waspurified by silica gel column chromatography (EtOAc/MeOH=10:1) to afford0.6 g (70%) of the acylated product 2b.

Characterization of Compounds 2:

Compound 2a, Methyl (7-azaindol-3-yl)-oxoacetate: ¹H NMR (300 MHz,DMSO-d₆) δ 8.60 (s, 1H), 8.47 (d, 1H, J=7.86 Hz), 8.40 (d, 1H, J=4.71Hz), 7.34 (dd, 1H, J=7.86, 4.77 Hz), 3.99 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 178.7, 163.3, 149.0, 145.1, 138.8, 129.7, 119.0, 118.0,111.2, 52.7. MS m/z: (M+H)⁺ calcd for C₁₀H₉N₂O₃: 205.06; found 205.04.HPLC retention time: 0.94 minutes (column A).

Compound 2b, Methyl (5azaindol-3-yl)-oxoacetate: ¹H NMR (500 MHz, CD₃OD)δ 9.61 (s, 1H), 9.02 (s, 1H), 8.59 (d, 1H, J=6.63 Hz), 8.15 (d, 1H,J=6.60 Hz), 4.00 (s, 3H); ¹³C NMR (125 MHz, CD₃OD) δ 178.9, 163.0,145.6, 144.2, 138.3, 135.0, 124.7, 116.3, 112.1, 53.8. MS m/z: (M+H)⁺calcd for C₁₀H₉N₂O₃: 205.06; found 205.04. HPLC retention time: 0.32minutes (column A).

Compound 2c, Methyl (6-azaindol-3-yl)-oxoacetate: MS m/z: (M+H)⁺ calcdfor C₁₀H₉N₂O₃: 205.06; found 205.14. HPLC retention time: 0.61 minutes(column A).

Compound 2d, Methyl (4-azaindol-3-yl)-oxoacetate: MS m/z: (M+H)⁺ calcdfor C₁₀H₉N₂O₃: 205.06; found 204.99. HPLC retention time: 0.34 minutes(column A).

Compound 2e, Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate: ¹H NMR (500MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.17 (d, 1H, J=5.35 Hz), 8.05 (d, 1H,J=5.30 Hz), 3.91 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ 178.4, 162.7,141.3, 140.9, 134.6, 133.0, 130.1, 115.4, 113.0, 52.8. MS m/z: (M+H)⁺calcd for C₁₀H₈ClN₂O₃: 239.02; found 238.97. HPLC retention time: 1.18minutes (column A).

Compound 2f, Methyl (7-methoxy-6-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ calcd for C₁₁H₁₁N₂O₄: 235.07; found 234.95. HPLC retention time:0.95 minutes (column A).

Compound 2h, Methyl (7-chloro-4-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ calcd for C₁₀H₈ClN₂O₃: 239.02; found 238.97. HPLC retention time:0.60 minutes (column A).

Compound 2i, Methyl (7-hydroxyl-4-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ calcd for C₁₀H₉N₂O₄: 221.06; found 220.96. HPLC retention time:0.76 minutes (column A).

Compound 2ak, Methyl (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate: MSm/z: (M+H)⁺ calcd for C₁₁H₁₀ClN₂O₃: 253.04; found 252.97. HPLC,retention time: 1.48 minutes (column B).

Preparation of compound 2j, Methyl(7-methoxyl-1-methyl-4-azaindol-3-yl)-oxoacetate: To a solution ofcompound 2j (27 mg) in 10 ml of dry DMF was added 4.4 mg of NaH. After 1hour, 26 mg of Mel was added and the mixture was stirred at roomtemperature for 10 hours. DMF was then removed under vaccum to provide acrude product 2j which was used in the further reaction withoutpurification.

Characterization of Compounds 2j:

Compound 2j, Methyl (7-methoxy-1-methyl-4-azaindol-3-yl)-oxoacetate: MSm/z: (M+H)⁺ calcd for C₁₂H₁₃N₂O₄: 249.09; found 249.33. HPLC retentiontime: 0.91 minutes (column A).

2) Preparation of Potassium Azaindole 3-Glyoxylate 3

Preparation of Potassium (7-azaindol-3-yl)-oxoacetate 3a: Compound 2a(43 g, 0.21 mol) and K₂CO₃ (56.9 g, 0.41 mol) were dissolved in MeOH(200 ml) and H₂O (200 ml). After 8 hours, product 3a precipitated outfrom the solution. Filtration afforded 43 g of compound 3a as a whitesolid in 90.4% yield.

Characterization of Compounds 3:

Compound 3a, Potassium (7-azaindol-3-yl)-oxoacetate: ¹H NMR (300 MHz,DMSO-d₆) δ 8.42 (d, 1H, J=7.86 Hz), 8.26 (d, 1H, J=4.71 Hz), 8.14 (s,1H), 7.18 (dd, 1H, J=7.86, 4.71 Hz); ¹³C NMR (75 MHz, DMSO-d₆) δ 169.4,148.9, 143.6, 135.1, 129.3, 118.2, 117.5, 112.9. MS m/z: (M+H)⁺ of thecorresponding acid of compound 3a (3a-K+H) calcd for C₉H₇N₂O₃: 191.05;found 190.97. HPLC retention time: 0.48 minutes (column A).

Compound 3b, Potassium (5-azaindol-3-yl)-oxoacetate: MS m/z: (M+H)⁺ ofthe corresponding acid of compound 3b (3b-K+H) calcd for C₉H₇N₂O₃:191.05; found 191.02. HPLC retention time: 0.13 minutes (column A).

Compound 3c, Potassium (6-azaindol-3-yl)-oxoacetate: MS m/z: (M+H)⁺ ofthe corresponding acid of compound 3c (3c-K+H) calcd for C₉H₇N₂O₃:191.05; found 190.99. HPLC retention time: 0.23 minutes (column A).

Compound 3d, Potassium (4-azaindol-3-yl)-oxoacetate: MS m/z: (M+H)⁺ ofthe corresponding acid of compound 3d (3d-K+H) calcd for C₉H₇N₂O₃:191.05; found 190.87. HPLC retention time: 0.19 minutes (column A).

Compound 3e, Potassium (7-chloro-6-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ of the corresponding acid of compound 3e (3e-K+H)⁺ calcd forC₉H₆ClN₂O₃: 225.01; found 224.99. HPLC retention time: 0.93 minutes(column A).

Compound 3f, Potassium (7-methoxy-6-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ of the corresponding acid of compound 3f (3f-K+H)⁺ calcd forC₁₀H₉N₂O₄: 221.06; found 220.97. HPLC retention time: 0.45 minutes(column A).

Compound 3h, Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate: MS m/z:(M+H)⁺ of the corresponding acid of compound 3h (3h-K+H)⁺ calcd forC₉H₆ClN₂O₃: 225.01; found 225.27. HPLC retention time: 0.33 minutes(column A).

Compound 3j, Potassium (7-methoxyl-1-methyl-4-azaindol-3-yl)-oxoacetate:MS m/z: (M+H)⁺ of the corresponding acid of compound 3j (3j-K+H)⁺ calcdfor C₁₁H₁₁N₂O₄: 235.07; found 235.01. HPLC retention time: 0.36 minutes(column A).

Compound 3ak, Potassium (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate:MS m/z: (M+H)⁺ of the corresponding acid of compound 3ak (3ak-K+H)⁺calcd for C₁₀H₈ClN₂O₃: 239.02; found 238.94. HPLC retention time: 1.24minutes (column B).

1) Preparation of Azaindole Piperazine Diamide 5 Typical Procedure forthe Preparation of Compounds in Scheme 3

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine 5a:Potassium 7-azaindole 3-glyoxylate 3a (25.4 g, 0.111 mol),(R)-3-methyl-N-benzoylpiperazine 4a (22.7 g, 0.111 mol),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (33.3 g,0.111 mol) and Hunig's Base (28.6 g, 0.222 mol) were combined in 500 mlof DMF. The mixture was stirred at room temperature for 8 hours.

DMF was removed via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate (2000 ml) and 5% Na₂CO₃ aqueoussolution (2×400 ml). The aqueous layer was extracted with ethyl acetate(3×300 ml). The organic phase combined and dried over anhydrous MgSO₄.Concentration in vacuo provided a crude product, which was purified bysilica gel column chromatography with EtOAc/MeOH (50:1) to give 33 g ofproduct 5a in 81% yield.

Typical Procedure for the Preparation of Compounds in Scheme 4

Preparation ofN-(benzoyl)-2-ethyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine 5b andN-(benzoyl)-2-ethyl-N′-[(7-azaindol-3-yl)-carbonyl]-piperazine 5c: To asolution of 7-azaindole 1a (1.0 g, 8.5 mmol) in dry diethyl ether (20ml), 3.1 ml of MeMgl (3.0M in Et₂O, 9.3 mmol) was added at roomtemperature. The resulting mixture was stirred at room temperature for 1hour before ZnCl₂ (1M in ether, 10.2 ml, 10.2 mmol) was added. One hourlater, oxalyl chloride (10.7 g, 85 mmol) was injected into the solutioncautiously. After the reaction was stirred for 8 hours, solvent andexcess oxayl chloride were removed under vaccum to give a residuecontaining a mixture of 6a and 7a.

After the residue was dissolved in dry CH₃CN (8 ml), mono-benzoylatedpiperazine 4b (0.25 g, 1.15 mmol) and pyridine (1 g, 12.7 mmol) wereadded into the solution subsequently. 1 hour later, solvents wereremoved and residue was purified using Shimadzu automated preparativeHPLC System to give compound 5b (20 mg, 0.6%) and compound 5c (16 mg,0.5%).

Characterization of Compounds 5 with the Following Sub-structure:

Compound 5a, n=2, R₇₋₁₃=H, R₁₄=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹HNMR (300 MHz, CD₃OD) δ 8.57 (d, 1H, J=5.97 Hz), 8.38 (d, 1H, J=4.20 Hz),8.27 (m, 1H), 7.47 (s, 5H), 7.35 (t, 1H, J=5.13 Hz), 4.75-2.87 (m, 7H),1.31 (b, 3H); ¹³C NMR (75 MHz, CD₃OD) δ 185.6, 172.0, 166.3, 148.9,144.6, 137.0, 134.8, 130.2, 129.9, 128.4, 126.6, 118.6, 118.0, 112.2,61.3, 50.3, 45.1, 35.5, 14.9, 13.7. MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃:377.16; found 377.18. HPLC retention time: 1.21 minutes (column A).

Compound 5ai, n=2, R₇₋₁₃=H, R₁₄=Me,N-(benzoyl)-3-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃: 377.16; found 377.05.

Compound 5b, n=2, R₇₋₈=R₁₀₋₁₄=H, R₉=Et,N-(benzoyl)-2-ethyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹H NMR(500 MHz, CD₃OD) δ 8.63 (s, 1H), 8.40 (s, 1H), 8.25 (m, 1H), 7.42 (m,6H), 4.70-2.90 (m, 7H), 1.80-0.60 (m, 5H); ¹³C NMR (125 MHz, CD₃OD) δ186.8, 174.2, 168.3, 149.6, 145.4, 138.8, 136.9, 132.6, 131.3, 130.0,128.0, 120.2, 117.7, 114.1, 58.4, 52.2, 47.5, 44.8, 23.0, 10.9, 10.7. MSm/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₃: 391.18; found 391.22. HPLC retentiontime: 1.35 minutes (column A).

Compound 5c, n=1, R₇₋₈=R₁₀₋₁₄=H, R₉=Et,N-(benzoyl)-2-ethyl-N′-[(7-azaindol-3-yl)-carbonyl]-piperazine: ¹H NMR(500 MHz, CD₃OD) δ 8.33 (m, 2H), 7.87 (s, 1H), 7.47 (m, 5H), 7.33 (m,1H), 4.74-2.90 (m, 7H), 1.78-0.75 (m, 5H); ¹³C NMR (125 MHz, CD₃OD) δ168.0, 164.2, 162.8, 147.0, 142.8, 136.9, 133.1, 132.8, 131.3, 130.4,130.0, 128.0, 118.4, 110.3, 57.0, 53.4, 46.7, 24.0, 10.7. MS m/z: (M+H)⁺calcd for C₂₁H₂₃N₄O₂: 363.18; found 363.22. HPLC retention time: 1.14minutes (column A).

Compound 5d, n=2, R₇₋₁₄=H,N-(benzoyl)-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹H NMR (500MHz, CD₃OD) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.46 (s, 5H),7.29 (m, 1H), 3.97-3.31 (m, 8H). MS m/z: (M+H)⁺ calcd for C₂₀H₁₉N₄O₃:363.15; found 363.24. HPLC retention time: 1.18 minutes (column A).

Compound 5e, n=2, R₇₋₈=R₁₀₋₁₄=H, R₉=Me,N-(benzoyl)-2-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹H NMR(500 MHz, CD₃OD) δ 8.64 (s, 1H), 8.51 (s, 1H), 8.28 (m, 1H), 7.42 (m,6H), 4.48-2.90 (m, 7H), 1.26 (m, 3H); ¹³C NMR (125 MHz, CD₃OD) δ 185.3,171.4, 166.8, 164.0, 147.9, 143.6, 137.3, 135.3, 131.2, 129.8, 128.4,126.2, 118.6, 112.4, 49.4, 45.9, 45.6, 45.1, 40.8, 40.4, 14.1. MS m/z:(M+H)⁺ calcd for C₂₁H₂₁N₄O₃: 377.16; found 377.21. HPLC retention time:1.26 minutes (column A).

Compound 5f, n=2, R₇₋₁₃=H, R₁₄=(S)-Me,(S)-N-(benzoyl)-3-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹HNMR (500 MHz, CD₃OD) δ 8.64 (s, 1H), 8.39 (s, 1H), 8.26 (m, 1H), 7.44(m, 6H), 4.71-3.79 (m, 7H), 1.26 (m, 3H); ¹³C NMR (125 MHz, CD₃OD) δ185.5, 171.9, 166.0, 158.4, 147.6, 143.5, 137.2, 134.8, 131.3, 129.8,128.3, 126.6, 118.6, 112.4, 50.3, 45.1, 41.2, 40.3, 14.9, 13.7. MS m/z:(M+H)⁺ calcd for C₂₁H₂₁N₄O₃: 377.16; found 377.21. HPLC retention time:1.25 minutes (column A).

Compound 5g, n=2, R₇₋₁₃=H, R₁₄=Et,N-(benzoyl)-3-ethyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹H NMR(500 MHz, CD₃OD) δ 8.65 (b, 1H), 8.40 (s, 1H), 8.27 (m, 1H), 7.46 (m,6H), 4.73-3.00 (m, 7H), 1.80-0.58 (m, 5H); ¹³C NMR (125 MHz, CD₃OD) δ187.1, 173.0, 168.0, 149.2, 145.0, 138.8, 136.4, 133.0, 131.4, 129.9,128.2, 120.2, 114.1, 57.5, 46.0, 43.0, 37.5, 23.0, 10.7. MS m/z: (M+H)⁺calcd for C₂₂H₂₃N₄O₃: 391.18; found 391.20. HPLC retention time: 1.33minutes (column A).

Compound 5h, n=2, R₇₋₁₂=H, R₁₃=R₁₄=Me,N-(benzoyl)-3,3-dimethyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₃: 391.18; found 390.98. HPLC retentiontime: 1.22 minutes (column A).

Compound 5i, n=2, R₇₋₈=R₁₀₋₁₃=H, R₉=R₁₄=Me,trans-N-(benzoyl)-2,5-dimethyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.58 (m, 1H), 8.37 (d, 1H, J=15.7 Hz), 8.25(m, 1H), 7.77 (m, 1H), 7.46 (m, 5H), 5.09-3.16 (m, 6H), 1.30 (m, 6H). MSm/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₃: 391.18; found 391.11. HPLC retentiontime: 1.22 minutes (column A).

Compound 5ab, n=2, R₇₋₉=R₁₀₋₁₃=H, R₁₄=i-Pr,N-(benzoyl)-3-iso-Propyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₃H₂₁N₄O₃: 405.19; found 405.22. HPLC retentiontime: 1.52 minutes (column A).

Compound 5ac, n=2, R₇₋₈=R₁₀₋₁₄=H, R₉=i-Pr,N-(benzoyl)-2-iso-Propyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₃H₂₅N₄O₃: 405.19; found 405.25. HPLC retentiontime: 1.53 minutes (column A).

Compound 5ad, n=1, R₇₋₈=R₁₀₋₁₄=H, R₉=i-Pr,N-(benzoyl)-2-iso-Propyl-N′-[(7-azaindol-3-yl)-carbonyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₂H₂₅N₄O₂: 377.20; found 377.23. HPLC retentiontime: 1.34 minutes (column A).

Compound 5ae, n=2, R₇₋₈=R₁₀₋₁₄=H, R₉=Pentyl,trans-N-(benzoyl)-2-Pentyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₅H₂₉N₄O₃: 433.22; found 433.42. HPLCretention time: 1.74 minutes (column A).

Characterization of Compounds 5 with the Following Sub-structure:

Compound 5j, R₁₄=H,N-(pyridin-2-yl)-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine: ¹H NMR(500 MHz, CD₃OD) δ 8.65-7.30 (m, 8H), 4.00-3.33 (m, 8H). MS m/z: (M+H)⁺calcd for C₁₉H₁₈N₅O₃: 364.14; found 364.08. HPLC retention time: 0.97minutes (column A).

Compound 5k, R₁₄=(R)-Me,(R)-N-(pyridin-2-yl)-3-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (300 MHz, CD₃OD) δ 8.67-7.38 (m, 8H), 4.76-3.00 (m, 7H), 1.35 (m,3H); ¹³C NMR (75 MHz, CD₃OD) δ 186.0, 168.9, 166.6, 152.9, 148.5, 144.0,138.7, 137.8, 131.8, 125.6, 124.0, 119.0, 112.9, 51.3, 50.9, 50.7, 46.7,46.2, 45.7, 42.6, 42.0, 41.8, 40.8, 36.6, 35.7, 15.5, 14.2. MS m/z:(M+H)⁺ calcd for C₂₀H₂₀N₅O₃: 378.16; found 378.14. HPLC retention time:1.02 minutes (column A).

Compound 5l, R₁₄=(R)-Me,(R)-N-(5-bromo-furan-2-yl)-3-methyl-N′-[(7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.59 (d, 1H, J=9.4 Hz), 8.37 (s, 1H), 8.26 (m,1H), 7.34 (d, 1H, J=10.1 Hz), 7.06 (s, 1H), 6.59 (s, 1H), 4.56-3.16 (m,7H), 1.30 (m, 3H); ¹³C NMR (125 MHz, CD₃OD) δ 187.2, 167.8, 161.0,150.1, 149.8, 145.8, 138.7, 132.1, 127.0, 120.5, 120.2, 119.8, 114.8,113.9, 51.8, 47.0, 42.0, 37.0, 16.6, 15.4. MS m/z: (M+H)⁺ calcd forC₁₉H₁₈BrN₄O₄: 445.05; found 445.18. HPLC retention time: 1.35 minutes(column A).

Characterization of Compound 5m:

Compound 5m,(R)-N-(benzoyl)-3-methyl-N′-[(5-azaindol-3-yl)-oxoacetyl]-piperazine: ¹HNMR (500 MHz, CD₃OD) δ 9.62 (b, 1H), 8.72 (m, 1H), 8.61 (d, 1H, J=4.5Hz), 8.16 (d, 1H, J=5.8 Hz), 7.51 (b, 6H), 4.90-3.10 (m, 7H), 1.35 (b,3H). MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃ 377.16, found 377.15. HPLCretention time: 0.89 minutes (column A).

Characterization of Compounds 5 with the Following Sub-structure:

Compound 5p, X=H, Y=H,N-(benzoyl)-N′-[(6-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z: (M+H)⁺calcd for C₂₀H₁₉N₄O₃ 363.15, found 363.09. HPLC retention time: 0.96minutes (column A).

Compound 5q, X=H, Y=Me,N-(benzoyl)-3-Methyl-N′-[(6-azaindol-3-yi)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃ 377.16, found 377.11. HPLC retentiontime: 0.99 minutes (column A).

Compound 5r, X=H, Y=(R)-Me,(R)-N-(benzoyl)-3-Methyl-N′-[(6-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃ 377.16, found 377.10. HPLC retentiontime: 0.99 minutes (column A).

Compound 5s, X=H, Y=(S)-Me,(S)-N-(benzoyl)-3-Methyl-N′-[(6-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃ 377.16, found 377.10. HPLC retentiontime: 1.00 minutes (column A).

Compound 5t, X=Cl, Y=H,N-(benzoyl)-N′-[(7-Chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₀H₁₈ClN₄O₃ 397.11, found 397.26. HPLC retentiontime: 1.60 minutes (column B).

Compound 5u, X=Cl, Y=(R)-Me,(R)-N-(benzoyl)-3-Methyl-N′-[(7-Chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₃ 411.12, found 411.16. HPLCretention time: 1.43 minutes (column A).

Compound 5v, X=OMe, Y=(R)-Me,(R)-N-(benzoyl)-3-Methyl-N′-[(7-Methoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₃ 407.17, found 407.13. HPLCretention time: 1.31 minutes (column A).

Characterization of Compounds 5 with the Following Sub-structure:

Compound 5w, X=H, Y=(R)-Me, Z=H,(R)-N-(benzoyl)-3-Methyl-N′-[(4-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₃ 377.16, found 377.14. HPLC retentiontime: 0.96 minutes (column A).

Compound 5x, X=CH₃, Y=(R)-Me, Z=H, (R)-N-(benzoyl)-3-Methyl-N[-(7-Methyl-4-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z: (M+H)⁺ calcdfor C₂₁H₂₁N₄O₃ 391.18, found 391.15. HPLC retention time: 1.15 minutes(column A).

Compound 5y, X=Cl, Y=(R)-Me, Z=H,(R)-N-(benzoyl)-3-Methyl-N′-[(7-Chloro-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₃ 411.12, found 411.04. HPLCretention time: 1.10 minutes (column A).

Compound 5z, X=OMe, Y=(R)-Me, Z=Me,(R)-N-(benzoyl)-3-Methyl-N′-[(7-Methoxy-1-methyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₃H₂₅N₄O₄: 421.19, found 421.05. HPLCretention time: 1.06 minutes (column A).

Compound 5ak,(R)-N-(benzoyl)-3-Methyl-N′-[(5-Chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₂ClN₄O₃ 425.24, found 425.04. HPLCretention time: 1.72 minutes (column B).

Typical Procedure for Preparation of Compounds in Scheme 5, 6 and 7 1)N-Oxide Formation (Equation 1, Scheme 5)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine8a: 10 g of 7-azaindole piperazine diamide 5a (26.6 mmol) was dissolvedin 250 ml acetone. 9.17 g of mCPBA (53.1 mmol) was then added into thesolution. Product 8a precipitated out from the solution as a white solidafter 8 hours and was collected via filtration. After drying undervacuum, 9.5 g of compound 8a was obtained in 91% yield. No furtherpurification was needed.

Characterization of Compound 8 with the Following Sub-structure:

Compound 8a, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (d, 1H, J=12.2 Hz), 8.26 (d, 1H, J=10.1Hz), 8.00 (d, 1H, J=7.41 Hz), 7.41 (s, 5H), 7.29 (m, 1H), 4.57-2.80 (m,7H), 1.19 (b, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 186.2, 170.0, 165.0,139.5, 136.9, 136.7, 135.5, 133.5, 129.7, 128.5, 126.9, 121.6, 119.9,113.6, 49.4, 44.3, 15.9, 14.8. MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₄:393.16; found 393.16. HPLC retention time: 1.05 minutes (column A).

Compound 8e, R=H,N-(benzoyl)-N′-[(7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z:(M+H)⁺ calcd for C₂₀H₁₉N₄O₄: 379.14; found 379.02. HPLC retention time:1.15 minutes (column A).

Compound 8c, R=(S)-Me,(S)-N-(benzoyl)-3-methyl-N′-[(7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₄: 393.16; found 393.05.

Compound 8d, R=Me,N-(benzoyl)-3-methyl-N′-[(7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₄: 393.16; found 393.05.

Characterization of Compound 8b:

Compound 8b,(R)-N-(benzoyl)-3-methyl-N′-[(6-oxide-6-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₄: 393.16; found 393.08. HPLCretention time: 1.06 minutes (column A).

2) Chlorination (Equation 2, Scheme 5)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-chloro-7-azaindol-3-yl)-oxoacetyl]-piperazine9a: 55 mg of 7-azaindole piperazine diamide N-Oxide (0.14 mmol) 8a wasdissolved in 5 ml of POCl₃. The reaction mixture was heated at 60° C.for 4 hours. After cooling, the mixture was poured into ice cooledsaturated NaHCO₃ solution and the aqueous phase was extracted with EtOAc(3×50 ml). The combined organic layer was dried over MgSO₄ andconcentrated under vacuum. The crude product was purified using aShimadzu automated preparative HPLC System to give compound 9a (15 mg,26%).

Characterization of Compound 9a:

Compound 9a,(R)-N-(benzoyl)-3-methyl-N′-[(4-chloro-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, DMSO-d₆) δ 13.27 (b, 1H), 8.46 (m, 2H), 7.43 (m, 6H),5.00-2.80 (m, 7H), 1.23 (b, 3H). MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₃:411.12; found 411.09. HPLC retention time: 1.32 minutes (column A).

3) Nitration of N-Oxide (Equation 10, Scheme 6)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-nitro-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine15a: N-oxide 8a (10.8 g, 27.6 mmol) was dissolved in 200 ml oftrifluoroacetic acid and 20 ml of fuming nitric acid. The reactionmixture was stirred for 8 hours and quenched with methanol. Afterfiltration, the filtrate was concentrated under vacuum to give crudeproduct 15a as a brown solid, which was carried to the next step withoutfurther purification. A small amount of crude product was purified usinga Shimadzu automated preparative HPLC System to give compound 3 mg ofcompound 15a.

Characterization of Compound 15 with the Following Sub-structure:

Compound 15a, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-nitro-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₀N₅O₆: 438.14; found 438.07. HPLCretention time: 1.18 minutes (column A).

Compound 15b, R=(S)-Me,(S)-N-(benzoyl)-3-methyl-N′-[(4-nitro-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₀N₅O₆: 438.14; found 438.02. HPLCretention time: 1.18 minutes (column A).

Compound 15c, R=Me,N-(benzoyl)-3-methyl-N′-[(4-nitro-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₀N₅O₆: 438.14; found 438.02. HPLCretention time: 1.18 minutes (column A).

4) Fluorination (Equation 5, Scheme 3)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-nitro-6-fluoro-7-azaindol-3-yl)-oxoacetyl]-piperazine10a: 20 mg of crude 4-nitro-7-azaindole piperazine diamide N-oxide 15aand an excess of Me₄NF (300 mg) were dissolved in 5 ml of DMSO-d₆. Thereaction mixture was heated at 100° C. for 8 hours. After cooling,DMSO-d₆ was removed by blowing nitrogen. The residue was partitionedbetween ethyl acetate (10 ml) and 2N NAOH solution (10 ml). The aqueousphase was extracted with EtOAc (2×10 ml). The organic layers werecombined and concentrated under vacuum to give a residue, which wasfurther purified using a Shimadzu automated preparative HPLC System togive compound of 10a (8.3 mg).

Characterization of Compound 10a:

Compound 10a:(R)-N-(benzoyl)-3-methyl-N′-[(4-nitro-6-fluoro-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (300 MHz, acetone-d₆) δ 8.44 (d, 1H, J=8.24 Hz), 7.47 (s, 6H),4.80-3.00 (m, 7H), 1.29 (b, 3H). MS m/z: (M+H)⁺ calcd for C₂₁H₁₉FN₅O₅:440.14; found 440.14. HPLC retention time: 1.40 minutes (column B).

5) Alkylation and Arylation (Equation 4, Scheme 5)

Preparation of (R)-N-(benzoyl)-3-methyl-N′-[(4 or6)-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine 11a: An excess of MeMgl(3M in THF, 0.21 ml, 0.63 mmol) was added into a solution of 7-azaindolepiperazine diamide N-oxide 8a (25 mg, 0.064 mmol). The reaction mixturewas stirred at room temperature and then quenched with methanol. Thesolvents were removed under vacuum, the residue was diluted withmethanol and purified using a Shimadzu automated preparative HPLC Systemto give compound 11a (6.7 mg, 27%).

Characterization of Compounds 11 with the Following Sub-structure:

Compound 11a: R=Me, (R)-N-(benzoyl)-3-methyl-N′-[(4 or6)-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z: (M+H)⁺ calcdfor C₂₂H₂₃N₄O₃: 391.18; found 391.17. HPLC retention time: 1.35 minutes(column B).

Compound 11b: R=Ph, (R)-N-(benzoyl)-3-methyl-N′-[(4 or6)-phenyl-7-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z: (M+H)⁺ calcdfor C₂₇H₂₅N₄O₃: 453.19; found 454.20. HPLC retention time: 1.46 minutes(column B).

Compound 11c, R=CH=CH₂, (R)-N-(benzoyl)-3-methyl-N′-[(4 or6)-vinyl-7-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z: (M+Na)⁺ calcdfor C₂₃H₂₂N₄NaO₃: 425.16; found 425.23. HPLC retention time: 1.12minutes (column A).

6) Nitrile Substitution and Chlorination (Equation 5, Scheme 5)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(6-chloro-7-azaindol-3-yl)-oxoacetyl]-piperazine9b and(R)-N-(benzoyl)-3-methyl-N′-[(6-cyano-7-azaindol-3-yl)-oxoacetyl]-piperazine12a: N-oxide 8a (0.20 g, 0.51 mmol) was suspended in 20 ml of dry THF,to which TMSCN (0.3 g, 3.0 mmol) and BzCl (0.28 g, 2.0 mmol) were added.The reaction mixture was stirred at room temperature for 2 hours, andthen heated at reflux for 5 hours. After cooling, the mixture was pouredinto 100 ml of saturated NaHCO₃ and the aqueous phase extracted withEtOAc (3×50 ml). The organic phase was combined and concentrated undervacuum to give a residue, which was diluted with methanol and purifiedusing a Shimadzu automated preparative HPLC System to give compound 12a(42 mg, 20%) and compound 9b (23 mg, 11%).

Characterization of Compounds 9b and 12a:

Compound 9b,(R)-N-(benzoyl)-3-methyl-N′-[(6-chloro-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (m, 2H), 7.42 (m, 6H), 5.00-2.80 (m,7H), 1.19 (b, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ 185.8, 170.0, 165.1,147.9, 145.1, 137.4, 135.4, 132.2, 129.5, 128.3, 126.8, 118.6, 116.1,111.8, 49.3, 47.2, 44.2, 15.6, 14.5. MS m/z: (M+H)⁺ calcd forC₂₁H₂₀ClN₄O₃: 411.12; found 411.09. HPLC retention time: 1.43 minutes(column A).

Compound 12a,(R)-N-(benzoyl)-3-methyl-N′-[(6-cyano-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (m, 2H), 7.86 (s, 1H), 7.42 (m, 5H),4.80-2.80 (m, 7H), 1.22 (b, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ 185.7,170.0, 164.8, 148.5, 140.9, 135.3, 130.3, 129.5, 128.3, 126.8, 126.2,123.0, 120.4, 118.0, 111.8, 49.4, 47.3, 44.2, 15.6, 14.5. MS m/z: (M+H)⁺calcd for C₂₂H₂₀N₅O₃: 402.16; found 402.13. HPLC retention time: 1.29minutes (column A).

7) Hydroxylation (Equation 6, Scheme 5)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(1-acetyl-6-acetoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine13a: 20 mg of 7-azaindole piperazine diamide N-oxide 8a was dissolved in5 ml of acetic anhydride (Ac₂O). The reaction mixture was heated atreflux for 8 hours. After cooling, the solvents were removed undervacuum to give product 13a, which was pure enough for further reactions.

Characterization of Compound 13a:

Compound 13a,(R)-N-(benzoyl)-3-methyl-N′-[(1-acetyl-6-acetoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (300 MHz, acetone-d₆) δ 8.67 (m, 2H), 7.47 (s, 5H), 7.27 (d, 1H,J=8.34 Hz), 4.90-2.80 (m, 7H), 2.09 (s, 6H), 1.30 (b, 3H); ¹³C NMR (75MHz, acetone-d₆) δ 187.0, 170.8, 169.0, 168.6, 164.9, 155.3, 136.5,134.7, 134.2, 133.2, 130.0, 129.8, 127.5, 118.9, 115.4, 113.8, 50.3,45.4, 41.3, 36.3, 25.5, 20.5, 16.0, 14.8. MS m/z: (M+Na)⁺ calcd forC₂₅H₂₄N₄O₆Na: 499.16; found 499.15. HPLC retention time: 1.46 minutes(column B).

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(6-hydroxyl-7-azaindol-3-yl)-oxoacetyl]-piperazine14a: The crude compound 13a and an excess of K₂CO₃ (100 mg) were mixedin MeOH and H₂O (1:1). The reaction mixture was stirred for 8 hours. TheMeOH was removed under vacuum, the aqueous phase extracted with EtOAc(3×10 ml) and the organic layers combined and concentrated. The crudeproduct was purified using a Shimadzu automated preparative HPLC Systemto give compound 1 mg of 14a (5% from compound 8a).

Characterization of Compound 14a:

Compound 14a,(R)-N-(benzoyl)-3-methyl-N′-[(6-hydroxyl-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₄: 393.16; found 393.12. HPLCretention time: 1.13 minutes (column A).

8) Thiol formation (Equation 7, Scheme 5)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(6-propylthio-7-azaindol-3-yl)-oxoacetyl]-piperazine17f. To an solution of 100 mg of compound 9a in 10 ml of CHCl₃ was addedTsCl (63 mg), and the solution was stirred for 5 minutes. Then, 2 ml ofpropylthiol was added and the reaction mixture was stirred for 8 hours.After concentration, the crude product was purified using a Shimadzuautomated preparative HPLC System to give compound 1.4 mg of 17f.

Characterization of Compound 17f:

Compound 17f,(R)-N-(benzoyl)-3-methyl-N′-[(6-propylthiol-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₄H₂₇N₄O₃S: 451.18; found 451.09. HPLCretention time: 1.45 minutes (column A).

9) Displacement of Nitro Group (Equation 11, Scheme 6)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine16a: 100 mg of crude compound 15a from the previous step was dissolvedin 6 ml of 0.5M MeONa in MeOH. The reaction mixture was refluxed for 8hours, and the solvent removed under vacuum to afford a mixtureincluding product 16a and other inorganic salts. This mixture was usedin the next step without further purification. A small portion of thecrude mixture was purified using a Shimadzu automated preparative HPLCSystem to give 5 mg of compound 16a.

Characterization of Compounds 16 with the Following Sub-structure:

Compound 16a, X=OMe, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₅ 423.17, found 423.04. HPLC retentiontime: 0.97 minutes (column A).

Compound 16f, X=OMe, R=(S)-Me,(S)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₅ 423.17, found 423.02.

Compound 16g, X=OMe, R=Me,N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₅ 423.17, found 423.03.

Compound 16b, X=OCH₂CF₃, R=(R)-Me, (R)-N-(benzoyl)-3-methyl-N′-[(4-(2,2,2-trifluoroethoxy)-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.44 (b, 1H), 8.30 (m, 1H), 7.50 (b, 5H), 7.14(b, 1H), 4.90-3.10 (m, 9H), 1.30 (m, 3H). MS m/z: (M+H)⁺ calcd forC₂₃H₂₂F₃N₄O₅: 491.15; found 491.16. HPLC retention time: 1.17 minutes(column A).

Compound 16c, X=OCH(CH₃)₂, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-(1-methylethoxy)-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.48 (s, 1H), 8.24 (m, 1H), 7.46 (m, 5H), 7.13(s, 1H), 5.03-3.00 (m, 8H), 1.49-1.15 (m, 9H). MS m/z: (M+H)⁺ calcd forC₂₄H₂₇N₄O₅: 451.20; found 451.21. HPLC retention time: 1.14 minutes(column A).

Compound 16d, X=OCH₂CH₃, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-ethoxy-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₃H₂₅N₄O₅: 437.18; found 437.13. HPLCretention time: 1.08 minutes (column A).

Compound 16e X=SCH₂CH₂CH₃, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-propylthio-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.24 (m, 2H), 7.45 (m, 5H), 7.25 (s, 1H),4.90-3.00 (m, 9H), 1.81 (b, 2H), 1.30 (m, 6H). MS m/z: (M+H)⁺ calcd forC₂₄H₂₇N₄O₄S: 467.18; found 467.14. HPLC retention time: 1.30 minutes(column A).

Compound 16h, X=NHMe, R=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-methylamino-7-oxide-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₄N₅O₄: 422.18; found 422.09. HPLCretention time: 1.19 minutes (column A).

10) Reduction of N-Oxide (Equation 12, Scheme 6)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine17a: 48 mg of crude 16a was suspended in 30 ml of ethyl acetate at roomtemperature. 1 ml of PCl₃ was added and the reaction was mixture stirredfor 8 hours. The reaction mixture was poured into ice cooled 2N NaOHsolution with caution. After separating the organic layer, the aqueousphase was extracted with EtOAc (6×80 ml). The organic layers werecombined, and concentrated in vacuo to give a residue which was purifiedusing a Shimadzu automated preparative HPLC System to give 38 mg ofcompound 17a.

Characterization of Compounds 17 with the Following Sub-structure:

Compound 17a, R=Ome, X=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (300 MHz, CD₃OD) δ 8.24 (d, 1H, J=5.7 Hz), 8.21 (m, 1H), 7.47 (s,5H), 6.90 (d, 1H, J=5.7 Hz), 4.71-3.13 (m, 10H), 1.26 (b, 3H); ¹³C NMR(75 MHz, CD₃OD) δ 185.3, 172.0, 167.2, 161.2, 150.7, 146.6, 135.5,134.8, 129.9, 128.3, 126.7, 112.8, 106.9, 100.6, 54.9, 50.2, 48.1, 45.1,14.5, 13.8. MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₄: 407.17; found 407.19.HPLC retention time: 1.00 minutes (column A).

Compound 17d, R=Ome, X=(S)-Me,(S)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₄: 407.17; found 407.03.

Compound 17e, R=Ome, X=Me,N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₄: 407.17; found 407.03.

Compound 17b, R=OCH₂CF₃, X=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-(2,2,2-trifluoroethoxy)-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.33 (s, 1H), 8.19 (m, 1H), 7.45 (m, 5H), 7.05(s, 1H), 4.90-3.00 (m, 9H), 1.29 (b, 3H); ¹³C NMR (125 MHz, CD₃OD) δ185.7, 174.0, 168.3, 162.0, 151.0, 146.1, 138.5, 136.4, 131.4, 130.0,128.2, 114.8, 109.5, 103.6, 67.2, 66.9, 52.0, 47.0, 16.4, 15.3. MS m/z:(M+H)⁺ calcd for C₂₃H₂₂F₃N₄O₄: 475.16; found 475.23. HPLC retentiontime: 1.22 minutes (column A).

Compound 17c, R=OCH(CH₃)₂, X=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-(1-methylethoxy)-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.42 (s, 1H), 8.24 (m, 1H), 7.47 (m, 5H), 7.21(s, 1H), 5.20-3.00 (m, 8H), 1.51 (b, 6H), 1.22 (b, 3H); ¹³C NMR (125MHz, CD₃OD) δ 185.4, 173.6, 167.9, 166.1, 145.3, 141.4, 138.2, 136.4,131.5, 129.7, 128.2, 113.9, 111.4, 104.0, 75.5. 54.4, 53.7, 51.8, 46.9,22.1, 16.4, 15.3. MS m/z: (M+H)⁺ calcd for C₂₄H₂₇N₄O₄: 435.20; found435.20. HPLC retention time: 1.15 minutes (column A).

Compound 17m, R=OCH₂CH₃, X=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-ethoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₃H₂₅N₄O₄: 421.19; found 421.13. HPLCretention time: 1.13 minutes (column A).

Compound 17g, R=SCH₂CH₂CH₃, X=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-propylthio-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₄H₂₇N₄O₄S: 451.18; found 451.13. HPLCretention time: 1.50 minutes (column A).

Compound 17h, R=NHMe, X=(R)-Me,(R)-N-(benzoyl)-3-methyl-N′-[(4-methylamino-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₄N₅O₃: 406.19; found 406.03. HPLCretention time: 1.19 minutes (column A).

Characterization of Compound 18a

Compound 18a,(R)-N-(benzoyl)-3-methyl-N′-[(4-nitro-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (300 MHz, CD₃OD) δ 8.58 (s, 1H), 8.53 (m, 1H), 7.64 (s, 1H), 7.47(s, 5H), 4.90-3.00 (m, 7H), 1.30 (b, 3H); ¹³C NMR (75 MHz, CD₃OD) δ184.1, 172.1, 165.6, 151.9, 149.6, 145.5, 139.4, 134.8, 129.7, 128.4,126.7, 111.6, 111.2, 107.4, 53.7, 48.4, 45.9, 15.0, 13.7. MS m/z: (M+H)⁺calcd for C₂₁H₂₀N₅O₅: 422.15; found 422.09. HPLC retention time: 1.49minutes (column B).

11) Reduction of Nitro to Hydoxylamine Group (Equation 14, Scheme 6)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-hydroxylamino-7-azaindol-3-yl)-oxoacetyl]-piperazine19a: 10 mg of Pd (10% on activated carbon) was added to a solution ofcompound 18a (48 mg, 0.11 mmol) in methanol (10 ml) under an atmosphereof hydrogen. The reaction mixture was stirred for 8 hours at roomtemperature. After filtration, the filtrate was concentrated in vacuo togive a residue which was purified using a Shimadzu automated preparativeHPLC System to give compound 19a (7.9 mg, 17%).

Characterization of Compound 19a:

Compound 19a,(R)-N-(benzoyl)-3-methyl-N′-[(4-hydroxylamino-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₂N₅O₄: 408.17; found 408.21. HPLCretention time: 1.03 minutes (column A).

12) Reduction of Nitro to Amine Group (Equation 15, Scheme 6)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-amino-7-azaindol-3-yl)-oxoacetyl]-piperazine20a: 114 mg of Na₂S.2H₂O (1 mmol) was added to a solution of compound18a (20 mg, 0.048 mmol) in MeOH (5 ml) and H₂O (5 ml). The reactionmixture was heated at reflux for 8 hours. After cooling, the reactionmixture was concentrated in vacuo to give a residue which was purifiedusing a Shimadzu automated preparative HPLC System to give 4 mg ofcompound 20a (21.3%).

Characterization of Compound 20a:

Compound 20a,(R)-N-(benzoyl)-3-methyl-N′-[(4-amino-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.16 (m, 1H), 8.01 (d, 1H, J=8.1 Hz), 7.47 (m,5H), 6.66 (s, 1H), 4.90-3.00 (m, 7H), 1.30 (b, 3H). MS m/z: (M+H)⁺ calcdfor C₂₁H₂₂N₅O₃: 392.17; found 392.14. HPLC retention time: 0.96 minutes(column A).

13) Alkylation of the Nitrogen Atom at Position 1 (Equation 16, Scheme7)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(1-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine21a: NaH (2 mg, 60% pure, 0.05 mmol) was added to a solution of compound5a (10 mg, 0.027 mmol) in DMF. After 30 minutes, Mel (5 mg, 0.035 mmol)was injected into the mixture via syringe. The reaction mixture wasstirred for 8 hours at room temperature and quenched with methanol. Themixture was partitioned between ethyl acetate (2 ml) and H₂O (2 ml). Theaqueous phase was extracted with EtOAc (3×2 ml). The organic layers werecombined, dried over anhydrous MgSO₄ and concentrated in vacuo to give acrude product which was purified using a Shimadzu automated preparativeHPLC System to give compound 21a (2.5 mg, 24%).

Characterization of Compound 21 with the Following Sub-structure:

Compound 21a, R=Me,(R)-N-(benzoyl)-3-methyl-N′-[(1-methyl-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.56 (b, 1H), 8.42 (s, 1H), 8.30 (m, 1H), 7.47(m, 6H), 4.90-3.00 (m, 7H), 3.96 (s, 3H), 1.28 (b, 3H). MS m/z: (M+Na)⁺calcd for C₂₂H₂₂N₄O₃Na: 413.16; found 413.15. HPLC retention time: 1.47minutes (column B).

Compound 21b, R=CH₂—CH=CH₂,(R)-N-(benzoyl)-3-methyl-N′-[(1-allyl-7-azaindol-3-yl)-oxoacetyl]-piperazine:¹H NMR (500 MHz, CD₃OD) δ 8.37 (m, 3H), 7.44 (m, 6H), 6.08 (m, 1H),5.22-3.06 (m, 11H), 1.27 (m, 3H); ¹³C NMR (75 MHz, CD₃OD) δ 184.2,184.1, 170.8, 165.0, 146.7, 143.5, 137.9, 133.8, 131.4, 129.2, 128.8,127.3, 125.6, 117.9, 117.4, 116.3, 110.3, 50.4, 49.7, 49.1, 45.7, 44.0,41.0, 39.6, 34.8, 14.0, 12.8. MS m/z: (M+H)⁺ calcd for C₂₄H₂₅N₄O₃:417.19; found 417.11. HPLC retention time: 1.43 minutes (column A).

14) Group Transfer Reactions from Halide (Equation 18, Scheme 8)

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(7-dimethylamino-6-azaindol-3-yl)-oxoacetyl]-piperazine27c: A mixture of compound 5u (50 mg) and 4 ml of dimethylamine (40% inwater) was heated to 150° C. in sealed tube for 18 hours. The solventswere then removed under vaccum and the residue was purified usingShimadzu automated preparative HPLC System to give 10 mg of compound27c.

Characterization of Compound 27c:

Compound 27c,(R)-N-(benzoyl)-3-methyl-N′-[(7-dimethylamino-6-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₃H₂₆N₅O₃ 420.20, found 420.16. HPLC retentiontime: 1.13 minutes (column A).

15) Modification of Benzoyl Moiety (Equation 26, Scheme 11)

Hydrolysis of benzoyl amide, preparation of(R)-2-methyl-N-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine 31a:Compound 17a (0.9 g) and KOH (2.0 g) were mixed in a solution of EtOH(15 ml) and water (15 ml). The reaction was refluxed for 48 hours.Solvents were removed under vaccum and the resulting residue waspurified by silica gel column chromatography (EtOAc/Et₃N=100:1 to 3:1)to afford 0.6 g of compound 31a.

Characterization of Compound 31a:

Compound 31a,(R)-2-methyl-N-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine: MSm/z: (M+H)⁺ calcd for C₁₅H₁₉N₄O₃ 303.15, found 303.09. HPLC retentiontime: 0.29 minutes (column A).

Diamide formation: Preparation of(R)-N-(4-azido-2,3,5,6-tetra-fluorobenzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine5n: Amine 31a (0.15 g), 4-azido-2,3,5,6-tetrafluorobenzoic acid (0.12g), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (0.15g) and Hunig's Base (0.5 ml) were combined in 5 ml of DMF. The mixturewas stirred at room temperature for 8 hours. Solvents were then removedunder vaccum and the residue was purified using Shimadzu automatedpreparative HPLC System to give 10 mg of compound 5n.

Characterization of Compound 5n:

Compound 5n,(R)-N-(4-azido-2,3,5,6-tetra-fluorobenzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₁₈F₄N₇O₄ 520.14, found 520.05. HPLCretention time: 1.42 minutes (column A).

Compound 5af, Ar=4, 5-dibromophenyl,(R)-N-(3,5-dibromobenzyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₂H₂₁Br₂N₄O₄ 562.99, found 562.99. HPLCretention time: 1.54 minutes (column A).

Compound 5ag, Ar=4-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl,(R)-N-[4-(3-(tifluoromethyl)-3H-diazirin-3-yl)benzyl]-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₄H₂₂F₃N₆O₄ 515.17, found 515.02. HPLCretention time: 1.55 minutes (column A).

New Equation:

Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-hydroxyl-7-azaindol-3-yl)-oxoacetyl]-piperazine5ah: The crude compound 17a (100 mg) and an excess of TMSI (0.25 ml)were mixed in CHCl₃. The reaction mixture was stirred for 6 days. Thesolvent was removed under vacuum, he crude product was purified using aShimadzu automated preparative HPLC System to give compound 4.4 mg of5ah.

Characterization of Compound 5ah:

Compound 5ah,(R)-N-(benzoyl)-3-methyl-N′-[(4-hydroxyl-7-azaindol-3-yl)-oxoacetyl]-piperazine:MS m/z: (M+H)⁺ calcd for C₂₁H₂₁N₄O₄: 393.16; found 393.11. HPLCretention time: 1.46 minutes (column B).

Alternate Procedures Useful for the Synthesis of Compound 39

Preparation of 5,7-dibromo-4-methoxy-6-azaindole 36: Vinylmagnesiumbromide (0.85 M in THF, 97.7 mL, 83.0 mmol) was added over 30 min. to astirring solution of 2,6-dibromo-3-methoxy-5-nitropyridine (7.4 g, 23.7mmol) in THF (160 mL) at −75° C. The solution was stirred 1 h at −75°C., overnight at −20° C., recooled to −75° C. and quenched withsaturated aqueous NH₄Cl (˜100 mL). The reaction mixture was allowed towarm to rt, washed with brine (˜100 mL) and extracted with Et₂O (150 mL)and CH₂Cl₂ (2×100 mL). The combined organics were dried (MgSO₄),filtered and concentrated. The residue was purified by flash columnchromatography (SiO₂, 3:1 hexanes/EtOAc) to yield5,7-dibromo-4-methoxy-6-azaindole 36 (1.10 g, 3.60 mmol, 15%) as a paleyellow solid.

Characterization of 36: ¹H NMR (500 MHz, CDCl₃) 8.73 (br s, 1H), 7.41(dd, J=3.1, 2.8 Hz, 1H), 6.69 (d, J=3.1, 2.2 Hz, 1H), 4.13 (s, 3H); ¹³CNMR (125 MHz, CDCl₃) 146.6, 133.7, 128.8, 127.5, 120.2, 115.6, 101.9,60.7. MS m/z (M+H)⁺ calcd for C₈H₇Br₂N₂O: 304.88; found 304.88. HPLCretention time: 1.31 minutes (column A).

Preparation of 4-methoxy-6-azaindole 37: A solution of5,7-Dibromo-4-methoxy-6-azaindole 36 (680 mg, 2.22 mmol), 5% Pd/C (350mg, 0.17 mmol) and hydrazine (2.5 mL, 80 mmol) in EtOH was heated atreflux for 1 h. The reaction mixture was allowed to cool to rt, filteredthrough celite and the filtrate concentrated. Aqueous NH₄OH (11% in H₂O,45 mL) was added to the residue and the solution was extracted withCH₂Cl₂ (3×30 mL). The combined organics were dried (MgSO₄), filtered andconcentrated to yield 4-methoxy-6-azaindole 37 (290 mg, 1.95 mmol, 88%)as an orange solid.

Characterization of 37: ¹H NMR (500 MHz, CDCl₃) 8.61 (br s, 1H), 8.52(s, 1H), 7.88 (s, 1H), 7.30 (d, J=2.9 Hz, 1H), 6.69 (d, J=2.9 Hz, 1H),4.03 (s, 3H). MS m/z (M+H)⁺ calcd for C₈H₉N₂O: 149.06; found 148.99.HPLC retention time: 0.61 minutes (column A).

Preparation of 38: Aluminum trichloride (67 mg, 0.50 mmol) was added toa solution of 4-methoxy-6-azaindole (15 mg, 0.10 mmol) in CH₂Cl₂ (2 mL)and stirred at rt for 30 min. Methyl chlorooxacetate (0.020 mL, 0.21mmol) was added and the reaction mixture was stirred overnight. Thereaction was quenched with MeOH (0.20 mL), stirred 5 h and filtered(flushing with CH₂Cl₂). The filtrate was washed with saturated aqueousNH₄OAc (2×10 mL) and H₂O (10 mL) and concentrated to yield 38 (5 mg) asa yellow solid.

Characterization of 38: ¹H NMR (500 MHz, CDCl₃) 8.65 (s, 1H), 8.36 (s,1H), 8.02 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H). MS m/z (M+H)⁺ calcd forC₁₁H₁₀N₂O₄: 235.06; found 234.96. HPLC retention time: 0.63 minutes(column A).

Preparation ofN-benzoyl-N′-[(2-carboxaldehyde-pyrrole-4-yl)-oxoacetyl]-piperazine 41:A solution of ethyl 4-oxoacetyl-2-pyrrolecarboxaldehyde 40 (17.0 g, 87.1mmol) in 25 mL of KOH (3.56 M in H₂O, 88.8 mmol) and EtOH (400 mL) wasstirred 2 h. The white precipitate that formed was collected byfiltration, washed with EtOH (˜30 mL) and Et₂O (˜30 mL) and dried underhigh vacuum to yield 15.9 g of potassium2-pyrrolecarboxaldehyde-4-oxoacetate as a white solid that was usedwithout further purification. A solution of potassium2-pyrrolecarboxaldehyde-4-oxoacetate (3.96 g, 19.3 mmol),N-benzoylpiperazine hydrochloride (4.54 g, 19.7 mmol),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (5.88 g, 19.7mmol) and triethylamine (3.2 mL, 23 mmol) in DMF (50 mL) was stirred 1d. The reaction mixture was filtered into H₂O (300 mL), extracted withCH₂Cl₂ (3×200 mL) and the combined organics were concentrated on arotary evaporator to remove the CH₂Cl₂. The crude material (still inDMF) was then diluted with H₂O (200 mL) and allowed to recrystallize for48 h. The solid was then collected by filtration and dried under highvacuum (P₂O₅) to yieldN-benzoyl-N′-[(2-carboxaldehyde-pyrrole-4-yl)-oxoacetyl]-piperazine 41(3.3 g, 9.7 mmol, 45% over two steps) as a light yellow solid. Nofurther purification was required.

Characterization of 41: ¹H NMR (500 MHz, CDCl₃) 9.79 (s, 1H), 9.63 (s,1H), 7.82 (s, 1H), 7.51-7.34 (m, 6H), 4.05-3.35 (m, 8H). MS m/z (M+H)⁺calcd for C₁₈H₁₈N₃O₄: 340.12; found 340.11. HPLC retention time: 1.04minutes (column A).

Preparation of 42:N-benzoyl-N′-[(2-carboxaldehyde-pyrrole-4-yl)-oxoacetyl]-piperazine 41(3.3 g, 9.7 mmol) was stirred as a slurry in EtOH (100 mL) for 15 min.,cooled to 0° C. and then reacted with glycine methyl ester hydrochloride(3.66 g, 29.2 mmol), triethylamine (1.50 mL, 11 mmol) and sodiumcyanoborohydride (672 mg, 10.7 mmol). The reaction mixture was allowedto warm to rt, stirred 24 h and poured into ice (˜400 mL). The solutionwas extracted with EtOAc (3×300 mL) and the combined organics werewashed with brine (300 mL), dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by preparative thin layerchromatography (SiO₂, 9:1 EtOAc/MeOH, R_(f)=0.2) to yield 42 (2.4 g, 5.8mmol, 60%) as a white solid.

Characterization of 42: ¹H NMR (500 MHz, CDCl₃) 9.33 (s, 1H), 7.49 (s,1H), 7.58-7.32 (m, 5H), 6.50 (s, 1H), 3.90-3.35 (m, 8H), 3.81 (s, 2H),3.74 (s, 3H), 3.40 (s, 2H). MS m/z (M+H)⁺ calcd for C₂₁H₂₅N₄O₅: 413.17;found 413.17. HPLC retention time: 0.84 minutes (column A).

Preparation of 43: Methyl ester 42 (485 mg, 1.17 mmol) and K₂CO₃ (325mg, 2.35 mmol) in MeOH (6 mL) and H₂O (6 mL) were stirred at rt for 3 h.The reaction mixture was then quenched with concentrated HCl (0.40 mL)and concentrated under high vacuum. Part of the solid residue (200 mg,0.37 mmol) was added to a stirring solution of P₂O₅ (400 mg, 1.4 mmol)in methanesulfonic acid (4.0 g, 42 mmol) (which had already been stirredtogether at 110° C. for 45 min.) at 110° C. and stirred for 15 min. Thereaction mixture was poured over crushed ice (˜20 g), stirred 1 h,basified with K₂CO₃ (5.0 g, 38 mmol), diluted with CH₂Cl₂ (20 mL), andbenzoyl chloride (1.0 mL, 8.5 mmol) and stirred 1 h. The reactionmixture was extracted with CH₂Cl₂ (3×20 mL) and the combined organicswere dried (Na₂SO₄) and concentrated under reduced pressure. The residuewas purified by preparative thin layer chromatography (SiO₂, EtOAc,R_(f)=0.5) to yield 43 (101 mg g, 0.21 mmol, 57%) as an off white solid.

Characterization of 43: MS m/z (M+H)⁺ calcd for C₂₇H₂₄N₄O₅: 485.17;found 485.07. HPLC retention time: 1.15 minutes (column A).

Preparation of 39. R=OMe,N-(Benzoyl)-N′-[(4-methoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine:

In a flask affixed with a Dean-Stark trap, p-toluenesulfonic acidhydrate (55 mg, 0.29 mmol) and benzene (5 mL) were heated to reflux for1 h. The solution was cooled to rt and reacted with 2,2-dimethoxypropane(0.10 mL, 0.81 mmol) and 43 (46 mg, 0.095 mmol). The reaction mixturewas stirred 1 h, diluted with CH₂Cl₂ (2 mL), stirred 30 min. and thenoxidized with tetrachlorobenzoquinone (150 mg, 0.61 mmol) and stirredovernight. The reaction mixture was poured into 5% aqueous NaOH (20 mL)and extracted with CH₂Cl₂ (3×25 mL). The combined organics were dried(Na₂SO₄) and concentrated under reduced pressure. The residue wassubjected to preparative thin layer chromatography (Et₂O), the baselinematerial was extracted and resubjected to preparative thin layerchromatography (SiO₂, 9:1 EtOAc/MeOH, R_(f)=0.15) to yield 39 (3 mg,0.008 mmol, 6%) as a white solid.

Compound 39, R=OMe,N-(Benzoyl)-3-methyl-N′-[(4-methoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine:

Characterization of 39: ¹H NMR (500 MHz, CD₃OD) 8.49 (s, 1H), 8.35 (s,1H), 7.98 (s, 1H), 7.53-7.38 (m, 5H), 4.02 (s, 3H), 3.97-3.42 (m, 8H).MS m/z (M+H)⁺ calcd for C₂₁H₂₃N₄O₅: 393.15; found 393.13. HPLC retentiontime: 0.85 minutes (column A).

Preparation of 5avN-(Benzoyl)-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazineand 5av′(R)-N-(Benzoyl)-3-methyl-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine

It should be noted that 2-chloro-5-fluoro-3-nitro pyridine may beprepared by the method in example 5B of reference 59 Marfat et.al. Thescheme below provides some details which enhance the yields of thisroute. The Bartoli chemistry in Scheme 1 was used to prepare the azaindole 1zz which is also detailed below.

Compound zz1′ (1.2 g, 0.01 mol) was dissolved in 2.7 ml of sulphuricacid at room temperature. Premixed fuming nitric acid (1 ml) andsulphuric acid was added dropwise at 5-10° C. to the solution ofcompound zz1′. The reaction mixture was heated to 85° C. for 1 hr, thencooled to room temperature and poured into ice (20 g). The yellow solidproduct zz2′ was collected by filtration, washed with water and dried inair to yield 1.01 g of compound zz2′.

Compound zz2′ (500 mg, 3.16 mmol) was dissolved in Phosphorusoxychloride (1.7 ml, 18.9 mmol) and DMF (Cat) at room temperature. Thereaction was heated to 110° C. for 5 hr. The excess POCl3 was removed invacuo. The residue was chromatographed on silica gel (CHCl3, 100%) toafford 176 mg of product zz3′.

Compound zz3′ (140 mg, 0.79 mmol) was dissolved in THF (5 ml) and cooledto −78° C. under N2. Vinyl magnesium bromide (1.0M in ether, 1.2 ml) wasadded dropwise. After the addition was completed, the reaction mixturewas kept at −20° C. for about 15 hr. The reaction was then quenched withsaturated NH₄Cl, extracted with EtOAc. The combined organic layer waswashed with brine, dried over MgSO4, concentrated and chromatographed toafford about 130 mg of compound 1zz.

The chemistry in Scheme 3 provided the derivatives which corresponds togeneral formula 5 and has a 6-aza ring and R₂=F and R₄=Cl. Inparticular, reaction of 2-chloro-5-fluoro-3-nitro pyridine with 3equivalents of vinyl Magnesium bromide using the typical conditionsdescribed herein will provide 4-fluoro-7-chloro-6-azaindole in highyield. Addition of this compound to a solution of aluminum trichloridein dichloromethane stirring at ambident temperature followed 30 minuteslater with chloromethyl or chloroethyl oxalate provided an ester.Hydrolysis with KOH as in the standard procedures herein provided anacid salt which reacted with piperazines 4 (for example 1-benzoylpiperazine) in the presence of DEPBT under the standard conditionsdescribed herein to provide the compound 5 described just above. Thecompound with the benzoyl piperazine isN-(benzoyl)-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazineand is compound 5av. The compound with the (R)-methyl benzoyl piperazineis 5av′(R)-N-(benzoyl)-3-methyl-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazineand is compound 5av′.

Characterization of 5avN-(benzoyl)-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazineand 5av′(R)-N-(benzoyl)-3-methyl-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine.

¹H NMR (500 MHz, CD3OD): 8.40 (s, 1H), 8.04 (s, 1H), 7.46 (bs, 5H),3.80˜3.50 (m, 8H). LC/MS: (ES+) m/z (M+H)⁺=415, RT=1.247.

¹H NMR (500 MHz, CD3OD): 8.42 (s, 1/2H), 8.37 (s, 1/2H), 8.03 (s, 1H),7.71˜7.45 (m, 5H), 4.72˜3.05 (m, 7H), 1.45˜1.28 (m, 3H). LC/MS: (ES+)m/z (M+H)⁺=429, RT=1.297. LC/MS Column: YMC ODS-A C18 S7 3.0×50 mm.Start %B=0, Final %B=100, Gradient Time=2 min, Flow rate=5 ml/min.Wavelength=220 nm. Solvent A=10% MeOH—90% H2O—0.1% TFA. Solvent B=90%MeOH—10% H2O—0.1% TFA.

Similarly compounds 5ay, 5az, 5abc and 5abd can be made:

5ayN-(benzoyl)-N′-[(4-fluoro-7-methoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine.

5azN-(benzoyl)-N′-[(4-fluoro-7-(N-methyl-carboxamido)-6-azaindol-3-yl)-oxoacetyl]-piperazine.

5abc(R)-N-(benzoyl)-3-methyl-N′-[(7-methoxy-4-azaindol-3-yl)-oxoacetyl]-piperazine.

5abd(R)-N-(benzoyl)-3-methyl-N′-[(7-(N-methyl-carboxamido)-4-azaindol-3-yl)-oxoacetyl]-piperazine.

Compounds 5an, 5ao and 5ap are described below.

Compound 1am, 4-bromo-7-chloro-6-azaindole (yellow solid) was preparedby the same method used for azaindole 1e but the starting materialemployed was 5-bromo-2-chloro-3-nitropyridine. (available from Aldrich,Co.). MS m/z: (M+H)⁺ calcd for C₇H₅BrClN₂: 230.93; found 231.15. HPLCretention time: 1.62 minutes (column B).

Compound 1an, 4-methoxy-7-chloro-6-azaindole and compound 1ao,4,7-dimethoxy-6-azaindole: A mixture of 4-bromo-7-chloro-6-azaindole (1g), Cul (0.65 g) and NaOMe (4 ml, 25%) in MeOH (16 ml) was heated at110-120° C. for 16 hours in a sealed tube. After cooling to ambienttemperature, the reaction mixture was neutralized with 1 N HCl toachieve pH7. The aqueous solution was extracted with EtOAc (3×30 ml).Then the combined organic layer was dried over MgSO₄ and concentrated invacuo to afford a residue, which was purified by silica gel (50 g)chromatography using 1:7 EtOAc: hexane as the eluent. (Column dimension:20 mm×30 cm) to give 0.3 g of 4-methoxy-7-chloro-6-azaindole (whitesolid) and 0.1 g of 4,7-dimethoxy-6-azaindole (white solid).

Compound 1an, 4-methoxy-7-chloro-6-azaindole. MS m/z: (M+H)⁺ calcd forC₈H₈ClN₂O: 183.03; found 183.09. HPLC retention time: 1.02 minutes(column B).

Compound 1ao, 4,7-dimethoxy-6-azaindole. ¹H NMR (500 MHz, CDCl₃) δ 7.28(m, 2H), 6.63 (m, 1H), 4.14 (s, 3H), 3.95 (s, 3H). MS m/z: (M+H)⁺ calcdfor C₉H₁₁N₂O₂: 179.08; found 179.05. HPLC retention time: 1.36 minutes(column B).

Compound 2an, Ethyl (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate wasprepared by the same method used for compound 2b but the startingmaterial employed was 4-methoxy-7-chloro-6-azaindole. The compound waspurified by silica gel chromotography using 2:3 EtOAc:hexane as theeluent to give a yellow oil. MS m/z: (M+H)⁺ calcd for C₁₂H₁₂ClN₂O₄:283.05; found 283.22. HPLC retention time: 1.37 minutes (column B).

Compound 2ao, Ethyl (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate wasprepared by the same method as used for compound 2b but the startingmaterial employed was 4,7-dimethoxy-6-azaindole. The compound waspurified by silica gel chromatography using 2:3 EtOAc:Hexane as theeluent to give a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 9.50 (s, 1H),8.21 (s, 1H), 7.47 (s, 1H), 4.39 (q, 2H, d=7.05 Hz), 4.13 (s, 3H), 3.93(s, 3H), 1.40 (t, 3H, d=7.2 Hz). MS m/z: (M+H)⁺ calcd for C₁₃H₁₅N₂O₅:279.10; found 279.16. HPLC retention time: 1.28 minutes (column B).

Compound 3an (which was a yellow solid), Potassium(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate was prepared by the samemethod used to prepare compound 3a except Ethyl(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate was used as the startingmaterial. MS m/z: (M+H)⁺ of the corresponding acid of compound 3an(M−K+H)⁺ calcd for C₁₀H₈ClN₂O₄: 255.02; found 255.07. HPLC retentiontime: 0.74 minutes (column A).

Compound 3ao (which was a yellow solid), Potassium(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was prepared by the samemethod used to prepare compound 3a except Ethyl(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was employed as the startingmaterial. MS m/z: (M+H)⁺ of the corresponding acid of compound 3ao(M−K+H)⁺ calcd for C₁₁H₁₁N₂O₅: 251.07; found 251.09. HPLC retentiontime: 0.69 minutes (column B).

Compound 5an,N-(benzoyl)-N′-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]piperazinewas prepared by the same method which was used to prepare compound 5aexcept that Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetatewas employed as the starting material to give a white solid. Thecompound was purified by silica gel chromatography using EtOAc as theeluting solvent. MS m/z: (M+H)⁺ calcd for C₂₁H₂₀ClN₄O₄: 427.12; found427.12. HPLC retention time: 1.28 minutes (column A).

Compound 5ao,N-(benzoyl)-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]piperazine wasprepared by the same method used to prepare compound 5a but the startingmaterial was Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate. Thecompound was purified by silica gel chromatography using EtOAc as theeluting solvent to give a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 13.0(s, 1H), 8.15 (s, 1H), 7.40 (m, 6H), 4.00 (s, 3H), 3.83 (s, 3H),3.63-3.34 (m, 8H); ¹³C NMR (125 MHz, DMSO-d₆) δ 185.5, 169.3, 166.5,146.2, 145.7, 136.6, 135.3, 129.6, 128.4, 126.9, 122.2, 122.1, 119.2,114.4, 56.8, 52.9, 45.5, 39.9. MS m/z: (M+H)⁺ calcd for C₂₂H₂₃N₄O₅:423.17; found 423.19. HPLC retention time: 1.33 minutes (column B).Anal. Calcd. For C₂₂H₂₁N₄O₅: C, 62.7; H, 5.02; N, 13.29. Found: C,61.92; H, 5.41; 13.01. Melting Point: 229.5-232° C.

Compound 5ap, {circle around(R)}N-(benzoyl)-3-methyl-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]piperazine(white solid) was prepared using the same method used to preparecompound 5a except that Potassium(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was used as the startingmaterial. MS m/z: (M+H)⁺ calcd for C₂₃H₂₅N₄O₅: 437.18; found 437.24.HPLC retention time: 1.37 minutes (column B).

The compounds of the present invention may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsand vehicles.

Thus, in accordance with the present invention there is further provideda method of treating and a pharmaceutical composition for treating viralinfections such as HIV infection and AIDS. The treatment involvesadministering to a patient in need of such treatment a pharmaceuticalcomposition comprising a pharmaceutical carrier and atherapeutically-effective amount of a compound of the present invention.

The pharmaceutical composition may be in the form oforally-administrable suspensions or tablets; nasal sprays, sterileinjectable preparations, for example, as sterile injectable aqueous oroleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally-acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this invention can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weightorally in divided doses. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

Abbreviations or Alternative Names TFA Trifluoroacetic Acid DMFN,N-Dimethylformamide THF Tetrahydrofuran MeOH Methanol Ether DiethylEther DMSO Dimethyl Sulfoxide EtOAc Ethyl Acetate Ac Acetyl Bz BenzoylMe Methyl Et Ethyl Pr Propyl Py Pyridine Hunig's BaseN,N-Diisopropylethylamine DEPBT3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)- one DEPC diethylcyanophosphate DMP 2,2-dimethoxypropane mCPBA meta-Chloroperbenzoic Acidazaindole 1H-Pyrrolo-pyridine 4-azaindole 1H-pyrrolo[3,2-b]pyridine5-azaindole 1H-Pyrrolo[3,2-c]pyridine 6-azaindole1H-pyrrolo[2,3-c]pyridine 7-azaindole 1H-Pyrrolo[2,3-b]pyridine

What is claimed is:
 1. A pharmaceutical composition useful for treatinginfection by HIV which comprises an antiviral effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof,and an antiviral effective amount of one or more AIDS treatment agentsselected from the group consisting of: (a) an AIDS antiviral agent; (b)an anti-infective agent; (c) an immunomodulator; and (d) HIV entryinhibitors; said compound of formula I has the structure

 wherein:

R₁, R₂, R₃, R₄ are each independently selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl,C₂-C₆ alkynyl, halogen, CN, phenyl, nitro, OC(O)R₁₅, C(O)R₁₅, C(O)OR₁₆,C(O)NR₁₇R₁₈, OR₁₉, SR₂₀ and NR₂₁R₂₂; R₁₅, is independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyland C₄-C₆ cycloalkenyl; R₁₆, R₁₉, and R₂₀ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁₋₆ alkylsubstituted with one to three halogen atoms, C₃-C₆ cycloalkyl, C₂-C₆alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl; provided the carbonatoms which comprise the carbon-carbon triple bond of said C₃-C₆ alkynylare not the point of attachment to the oxygen or sulfur to which R₁₆,R₁₉, or R₂₀ is attached; R₁₇ and R₁₈ are each independently selectedfrom the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₆ alkenylor the carbon-carbon triple bond of said C₃-C₆ alkynyl are not the pointof attachment to the nitrogen to which R₁₇ and R₁₈ is attached; R₂₁ andR₂₂ are each independently selected from the group consisting of H, OH,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, C₃-C₆alkynyl, and C(O)R₂₃; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₂₁ and R₂₂ is attached; R₂₃ isselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl; R₅ is (O)_(m),wherein m is 0 or 1; n is 1 or 2; R₆ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl,C(O)R₂₄, C(O)OR₂₅, C(O)NR₂₆R₂₇, C₃-C₆ alkenyl, and C₃-C₆ alkynyl;provided the carbon atoms which comprise the carbon-carbon double bondof said C₃-C₆ alkenyl or the carbon-carbon triple bond of said C₃-C₆alkynyl are not the point of attachment to the nitrogen to which R₆ isattached; R₂₄ is selected from the group consisting of H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl;R₂₅ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl;provided the carbon atoms which comprise the carbon-carbon triple bondof said C₃-C₆ alkynyl are not the point of attachment to the oxygen towhich R₂₅ is attached; R₂₆ and R₂₇ are each independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl,C₅-C₆ cycloalkenyl, and C₃-C₆ alkynyl; provided the carbon atoms whichcomprise the carbon-carbon double bond of said C₃-C₆ alkenyl, C₅-C₆cycloalkenyl, or the carbon-carbon triple bond of said C₃-C₆ alkynyl arenot the point of attachment to the nitrogen to which R₂₆ and R₂₇ areattached; R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl, CR₂₈R₂₉OR₃₀, C(O)R₃₁,CR₃₂(OR₃₃)OR₃₄, CR₃₅NR₃₆R₃₇, C(O)OR₃₈, C(O)NR₃₉R₄₀, CR₄₁R₄₂F, CR₄₃F₂ andCF₃; R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₅, R₄₁, R₄₂ and R₄₃ are eachindependently selected from the group consisting of H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl andC(O)R₄₄; R₃₃, R₃₄ and R₃₈ are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆cycloalkenyl, and C₃-C₆ alkynyl; provided the carbon atoms whichcomprise the carbon-carbon triple bond of said C₃-C₆ alkynyl are not thepoint of attachment to the oxygen to which R₃₄ and R₃₈ are attached; R₃₆and R₃₇ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₃₆ and R₃₇ are attached; R₃₉ andR₄₀ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₃₉ and R₄₀ are attached; R₄₄ isselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl; Ar is selectedfrom the group consisting of

A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄, C₁, C₂, C₃, D₁, D₂, and D₃ are eachindependently selected from the group consisting of H, CN, halogen, NO₂,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆alkynyl, OR₄₅, NR₄₆R₄₇, SR₄₈, N₃ and CH(—N═N—)—CF₃; R₄₅ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl,C₄-C₆ cycloalkenyl and C₃-C₆ alkynyl; provided the carbon atoms whichcomprise the carbon-carbon triple bond of said C₃-C₆ alkynyl are not thepoint of attachment to the oxygen to which R₄₅ is attached; R₄₆ and R₄₇are each independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, C₃-C₆alkynyl and C(O)R₅₀; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₅-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₄₆ and R₄₇ are attached; R₄₈ isselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₃-C₆ alkynyl and C(O)R₄₉; providedthe carbon atoms which comprise the carbon-carbon triple bond of saidC₃-C₆ alkynyl are not the point of attachment to the sulfur to which R₄₈is attached; R₄₉ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and R₅₀ is selectedfrom the group consisting of H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl. 2.The pharmaceutical composition of claim 1, wherein the compound I isselected from the group consisting of compounds 5a, 5b, 5c, 5d, 5e, 5f,5g, 5h, 5i and 5ai as identified below:

Compd # n R 5a 2 R₇₋₁₃ = H, R₁₄ = (R)-Me 5b 2 R₇₋₈ = R₁₀₋₁₄ = H, R₉ = Et5c 1 R₇₋₈ = R₁₀₋₁₄ = H, R₉ = Et 5d 2 R₇₋₁₄ = H 5e 2 R₇₋₈ = R₁₀₋₁₄ = H,R₉ = Me 5f 2 R₇₋₁₃ = H, R₁₄ = (S)-Me 5g 2 R₇₋₁₃ = H, R₁₄ = Et 5h 2 R₇₋₁₂= H, R₁₃ = R₁₄ = Me 5i 2 R₇₋₈ = R₁₀₋₁₃ = H, R₉ = R₁₄ = Me 5ai 2 R₇₋₈ =R₉₋₁₃ = H, R₁₄ = Me.


3. The pharmaceutical composition of claim 1, wherein the compound I isselected from the group consisting of compounds 5j, 5k and 5l asidentified below:

Compound # R₁₄ Ar 5j H

5k (R)-Me

5l (R)-Me


4. The pharmaceutical composition of claim 1, wherein the compound I hasthe formula 5m identified below:


5. The pharmaceutical composition of claim 1, wherein the compound I isselected from the group consisting of compounds 8a, 15a, 16a, 16d and16e identified below:

Compound # R₂  8a H 15a NO₂ 16a OMe 16d OEt 16e SPr.


6. The pharmaceutical composition of claim 1, wherein the compound I isselected from the group consisting of compounds 9a, 9b, 10a, 11a, 11b,11c, 12a, 14a, 17a-17f, 18a, 19a and 20a identified below:

Compound # R₂ R₄ R₁₄  9a Cl H (R)-Me  9b H Cl (R)-Me 10a NO₂ F (R)-Me11a H (when R₄ = Me), Me (when R₂ = H), H (R)-Me Me (when R₄ = H) (whenR₂ = Me) 11b H (when R₄ = Ph), Ph (when R₂ = H), H (R)-Me Ph (when R₄ =H) (when R₂ = Ph) 11c H (when R₄ = vinyl), Vinyl (when R₂ = H), H (R)-MeVinyl (when R₄ = H) (when R₂ = Vinyl) 12a H CN (R)-Me 14a H OH (R)-Me17a OMe H (R)-Me 17d OMe H (S)-Me 17e OMe H Me 17b OCH₂CF₃ H (R)-Me 17cO-i-Pr H (R)-Me 17f H PrS (R)-Me 18a NO₂ H (R)-Me 19a NHOH H (R)-Me 20aNH₂ H (R)-Me.


7. The pharmaceutical composition of claim 5, wherein in compound I R₂is —OMe, R₄ is hydrogen, and R₁₄ is (R)-methyl.
 8. The pharmaceuticalcomposition of claim 1, wherein the compound I is selected from thegroup consisting of compounds 13a, 21a, and 21b identified below:


9. The pharmaceutical composition of claim 1, wherein in compound I R₂,R₃ and R₄ are each independently selected from the group consisting ofH, —OCH₃, —OCH₂CF₃, OiPr, —OnPr, halogen, CN, NO₂, C₁-C₆ alkyl, NHOH,NH₂, Ph, SR₂₀, and N(CH₃)₂.
 10. The pharmaceutical composition of claim9, wherein in compound I n is 2; R₁ is selected from the groupconsisting of H, C₁-C₆ alkyl and CH₂CH═CH₂; and R₅ is (O)_(m) wherein mis
 0. 11. The pharmaceutical composition of claim 10, wherein incompound I R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are eachindependently H or CH₃, provided one or two of the members of the groupR₇-R₁₄ are CH₃ and the remaining members of the group R₇-R₁₄ are H. 12.The pharmaceutical composition of claim 11, wherein in compound I one ofthe members of the group A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄, C₁, C₂, C₃,D₁, D₂, and D₃ is selected from the group consisting of hydrogen,halogen and amino and the remaining members of the group A₁, A₂, A₃, A₄,A₅, B₁, B₂, B₃, B₄, C₁, C₂, C₃, D₁, D₂, and D₃ are hydrogen.
 13. Thepharmaceutical composition of claim 1, wherein compound I has theFormula below:

wherein: R₂ is selected from the group consisting of H, —OCH₃, —OCH₂CF₃,—OPr, halogen, CN, NO₂, and NHOH; R₄ is selected from the groupconsisting of H, -halogen, —CN, and hydroxy; and R₁₄ is CH₃ or H. 14.The pharmaceutical composition of claim 1, wherein in compound I R₄ isselected from the group consisting of OH, CN, halogen, —OCOCH₃, andC₁-C₆ alkyl.
 15. The pharmaceutical composition of claim 1, whereincompound I has the formula identified below:

wherein: R₂ is selected from the group consisting of H, F, Cl, Br, OMe,CN, and OH; R₄ is selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, Cl, OMe, CN, OH,C(O)NH₂, C(O)NHMe, C(O)NHEt, phenyl and —C(O)CH₃; n is 2; R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, and R₁₄ are each independently H or CH₃, provided 0-2 ofthe members of the group R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ may be CH₃and the remaining members of the group R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, andR₁₄ are H; and R₆ is H or CH₃.
 16. The pharmaceutical composition ofclaim 1, wherein compound I is selected from the group consisting ofcompounds 5p, 5r, 5s, 5q, 5t, 5u, 5v, 27c, 5an, 5ao and 5ap identifiedbelow:

Compound # R₄ R₁₄ R₂ 5p H H H 5r H (R)-Me H 5s H (S)-Me H 5q H Me H 5tCl H H 5u Cl (R)-Me H 5v Ome (R)-Me H 27c Nme₂ (R)-Me H 5an Cl H Ome 5aoOme H Ome 5ap Ome Me  Ome.


17. The pharmaceutical composition of claim 1, wherein compound I hasthe formula:

wherein: R₄ is selected from the group consisting of H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, Cl, OMe, CN, OH,C(O)NH₂, C(O)NHMe, C(O)NHEt, phenyl and —C(O)CH₃; n is 2; R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, and R₁₄ are each independently H or CH₃, provided 0-2 ofthe members of the group R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ may be CH₃and the remaining members of the group R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, andR₁₄ are H; and R₆ is H or CH₃.
 18. The pharmaceutical composition ofclaim 1, wherein compound I is selected from the group consisting ofcompounds 5w, 5x, 5y, 5z and 5ak identified below:

Compound # R₃ R₄ R₆ 5w H H H 5x H Me H 5y H Cl H 5z H OMe Me 5ak Cl MeH.


19. The pharmaceutical composition of claim 15, wherein in compound IR₄, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are H; and R₂ is —OMe. 20.The pharmaceutical composition of claim 15, wherein in compound I R₂,R₄, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are H.
 21. The pharmaceuticalcomposition of claim 1, wherein compound I has the formula

wherein: R₂ is H, F, Cl, Br, OMe, CN, or OH; R₄ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, Cl, OMe, CN, OH, C(O)NH₂,C(O)NHMe, C(O)NHEt, Ph or —C(O)CH₃; n is 2; R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃and R₁₄ are each independently H or CH₃, provided up to two of thesesubstituents may be methyl; R₁ is hydrogen; R₅ is unsubstituted; and R₆is hydrogen or methyl.
 22. The pharmaceutical composition of claim 1,wherein compound I has the formula

wherein: R₂ is H, —OCH₃, —OCH₂CF₃, —OPr, halogen, CN, NO₂, or NHOH; R₄is H, -halogen, —CN, or hydroxy; One or two members of R₇-R₁₄ is methyland the remaining members are hydrogen; n is 2; R₁ is hydrogen; R₅ is(O)_(m), where m is O; and R₆ is hydrogen, methyl, or allyl.
 23. Amethod for treating mammals infected with the HIV virus, comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, incombination, with an antiviral effective amount of an AIDS treatmentagent selected from the group consisting of: an AIDS antiviral agent; ananti-infective agent; an immunomodulator; and HIV entry inhibitors;wherein said compound of Formula I is as defined in any of claims 1-22.